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Inheritance

1

Autosomal recessive inheritance HP:0000007

All three CNDD genocopies require biallelic loss-of-function variants. Heterozygous carriers are clinically unaffected under adequate dietary NAD precursor intake, but mouse data show that maternal heterozygosity combined with dietary vitamin B3 restriction is sufficient to cause malformations, so carrier status is not phenotypically inert under nutritional stress.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"CNDD is inherited in an autosomal recessive manner."

GeneReviews states the mode of inheritance for the disorder.

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Subtypes

3

Vertebral, cardiac, renal, and limb defects syndrome 1 (HAAO) MONDO:0060554

HAAO hgnc:4796

Caused by biallelic HAAO variants that abolish 3-hydroxyanthranilate 3,4-dioxygenase, the enzyme converting 3-hydroxyanthranilic acid to the quinolinate precursor. The block sits several enzymatic steps upstream of NAD, and 3-hydroxyanthranilic acid is predicted to accumulate behind it.

Show evidence (1 reference)

PMID:28792876 SUPPORT Human Clinical

"Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21)."

The founding report identifies biallelic HAAO loss-of-function variants in affected individuals.

Vertebral, cardiac, renal, and limb defects syndrome 2 (KYNU) MONDO:0060555

KYNU hgnc:6469

Caused by biallelic KYNU variants that abolish kynureninase, blocking conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. The accumulating 3-hydroxykynurenine is shunted to xanthurenic acid, which is excreted in urine and can be used diagnostically.

Show evidence (1 reference)

PMID:34200361 SUPPORT Human Clinical

"we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU in an individual presenting with overlapping features of VCRL and Catel-Manzke Syndrome"

Documents a biallelic KYNU lesion producing the VCRL phenotype.

Vertebral, cardiac, renal, and limb defects syndrome 3 (NADSYN1) MONDO:0030077

NADSYN1 hgnc:29832

Caused by biallelic NADSYN1 variants that abolish NAD synthetase 1, the terminal step shared by the de novo and Preiss-Handler routes. Because the block is downstream of the point at which dietary nicotinic acid enters, nicotinic acid is predicted not to rescue a NADSYN1-null individual. That vitamer specificity was shown in Nadsyn1-null mice and has not been tested in humans. This is the most phenotypically variable subtype, spanning prenatal lethality to individuals with no malformation at all.

Show evidence (4 references)

PMID:31883644 SUPPORT Human Clinical

"we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway"

Establishes NADSYN1 as the third CNDD gene.

PMID:36951206 SUPPORT Human Clinical

"two of them being siblings with the same homozygous variant and presenting with either a very severe prenatal lethal or a mild phenotypic form"

Documents the wide intrafamilial phenotypic variability that distinguishes the NADSYN1 subtype.

PMID:36649848 SUPPORT Human Clinical

"We present a male patient age 30 with a height of 130 cm and numerous skeletal malformations including segmentation defects of the spine, rib anomalies and unequal leg length as well as bilateral ptosis, cleft palate and asymmetric dysmorphic facial features."

Documents survival to adulthood in this subtype, against a literature otherwise dominated by infant deaths.

+ 1 more reference

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Discussions and Knowledge Gaps

4

Does periconceptional and gestational vitamin B3 supplementation prevent congenital NAD deficiency disorder in an at-risk human pregnancy?

KNOWLEDGE GAP human_efficacy_of_antenatal_b3_prevention

Attached to

treatments#Antenatal NAD precursor supplementation pathophysiology#Embryonic NAD Deficiency

Prevention in mice is well established and the mechanism is clear, but no trial or observational cohort has tested whether supplementation in a subsequent pregnancy after an affected child prevents recurrence. The only human data are population-level: a meta-analysis of 14 case-control studies associates insufficient maternal niacin intake with congenital anomalies in general (PMID:34748060), which is a different and much weaker claim. The gap matters because the intervention is cheap and low-risk while the outcome it would prevent is often lethal, and because families are being counselled now on mouse data alone. It is also unusually hard to close, since the disorder is rare enough that a conventional randomized trial is unlikely to be feasible.

Show evidence (1 reference)

PMID:38357931 SUPPORT Human Clinical

"Additional clinical trials are needed before accurate dosage recommendations required to prevent CNDD-dependent malformation can be made."

The authors state the human evidence is absent, which is the gap this discussion records.

Does the mouse dependence of the CNDD phenotype on maternal dietary NAD precursor restriction hold in humans, whose background vitamin B3 intake is generally higher and often fortified?

HUMAN MODEL MISMATCH mouse_diet_conditionality_vs_human_ascertainment

Attached to

pathophysiology#Insufficient Maternal NAD Precursor Provision animal_models#Haao-null mouse

In every mouse model the malformation phenotype is conditional on a B3-restricted maternal diet; null animals on a replete diet are largely protected. Human CNDD patients, by contrast, are ascertained without any documented maternal dietary deficiency. Either human de novo synthesis contributes a larger share of embryonic NAD than the mouse experiments imply, or unmeasured variation in maternal precursor status is doing work that nobody has quantified. Which of these is true determines whether maternal nutritional assessment belongs in the counselling of an at-risk family, so this is not merely a modelling curiosity.

Show evidence (1 reference)

PMID:32015132 SUPPORT Model Organism

"C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy."

Documents the dietary conditionality of the mouse phenotype that this mismatch is about.

Which NAD-dependent processes actually fail in the embryo when NAD falls, and why do they fail in these organs and not others?

KNOWLEDGE GAP unestablished_downstream_effectors_of_embryonic_nad_loss

Attached to

pathophysiology#Embryonic NAD Deficiency phenotypes#Developmental delay or intellectual disability

Every node in this entry below Embryonic NAD Deficiency is an organ-level description. The layer that would connect them, the NAD-dependent effectors in a proliferating embryonic progenitor (PARP-mediated ADP-ribosylation, sirtuin signalling, redox and ATP supply), is not curated here because it has not been established. It also has to explain a selectivity problem: NAD is required in every cell, yet the malformations fall on a specific and reproducible set of organs. Until this is resolved, the pathograph explains that NAD deficiency causes the malformations, not how, and any downstream node here should be read as a description rather than a mechanism.

Show evidence (1 reference)

PMID:39829932 SUPPORT Model Organism

"However, the mechanism by which NAD+ deficiency causes CNDD developmental anomalies has not been determined, nor has NAD+ deficiency been definitively linked to VACTERL association."

States directly that the mechanism connecting the NAD deficit to the anomalies is unknown, which is the gap this discussion records.

Is NAD deficiency a shared mechanism behind other recurrent malformation constellations currently classified as separate entities?

KNOWLEDGE GAP nad_deficiency_as_pleiotropic_malformation_mechanism

Attached to

disease#Congenital Vertebral-Cardiac-Renal Anomalies Syndrome

It has been proposed that NAD deficiency is a pleiotropic mechanism uniting VACTERL, limb-body wall complex, OEIS complex, MURCS, sirenomelia and others. The proposal is explicitly a hypothesis, and its author states that no confirmatory experimental studies in humans exist. Recording it as an open question rather than as background is the honest treatment: if it were true, the scope of this entry would be considerably larger than three genes.

Show evidence (1 reference)

PMID:35484986 SUPPORT Other

"it is important to emphasize there have been no confirmatory experimental studies in humans to prove this hypothesis."

The proposing author states the hypothesis is unconfirmed, which is why it is recorded as an open question rather than as content.

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Pathophysiology

9

De Novo NAD Synthesis Pathway Enzymatic Block

Biallelic loss-of-function variants in HAAO, KYNU or NADSYN1 abolish one of three non-redundant enzymatic steps converting L-tryptophan to NAD through the kynurenine pathway. No parallel route bypasses the lost step within de novo synthesis, so flux through the pathway stops at the affected enzyme.

HAAO hgnc:4796 KYNU hgnc:6469 NADSYN1 hgnc:29832

de novo NAD biosynthesis from L-tryptophan GO:0034354 ↓ DECREASED

3-hydroxyanthranilate 3,4-dioxygenase activity GO:0000334 ⇓ LOSS OF FUNCTION kynureninase activity GO:0030429 ⇓ LOSS OF FUNCTION NAD+ synthase activity GO:0008795 ⇓ LOSS OF FUNCTION

Animal models

Nadsyn1-null mouse Mouse recapitulates Reproduces NADSYN1-dependent CNDD and shows that the position of the block determines which precursors can bypass it.

Downstream

Kynurenine Pathway Intermediate Accumulation Substrate immediately upstream of the lost enzyme accumulates.

Embryonic NAD Deficiency

Show evidence (1 reference)

PMID:38357931 SUPPORT Human Clinical

"All CNDD cases identified to date originate from biallelic loss-of-function variants in any of 3 nonredundant genes of the NAD de novo synthesis pathway"

States the shared molecular lesion and its non-redundancy.

Kynurenine Pathway Intermediate Accumulation

Metabolites immediately upstream of the enzymatic block accumulate and spill into plasma and urine. The identity of the accumulating species is gene-specific, which is what makes the circulating NAD metabolome diagnostically informative: HAAO loss raises 3-hydroxyanthranilic acid, KYNU loss raises 3-hydroxykynurenine and its transamination product xanthurenic acid, and NADSYN1 loss raises the terminal precursor deamido-NAD (nicotinate adenine dinucleotide).

Show evidence (2 references)

PMID:34200361 SUPPORT Human Clinical

"Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis."

Demonstrates that the upstream intermediate accumulates measurably in a KYNU-deficient patient.

PMID:38357931 SUPPORT Other

"The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification."

Supports the diagnostic use of the accumulated-metabolite pattern.

Insufficient Maternal NAD Precursor Provision

NAD available to the conceptus depends on maternal circulating tryptophan and vitamin B3 vitamers, which reach the embryo via the yolk sac before the embryonic liver is functional. Low maternal precursor supply lowers embryonic NAD independently of the embryo's own genotype, and is the environmental arm of the gene-environment interaction that sets phenotype severity.

Animal models

Slc6a19 heterozygous mouse Mouse recapitulates Models the maternal-supply arm rather than the embryonic enzymatic block, producing CNDD malformations through restricted tryptophan transport.

Downstream

Embryonic NAD Deficiency

Show evidence (1 reference)

PMID:32015132 SUPPORT Model Organism

"C57BL/6J wild-type mice had offspring exhibiting similar malformations when their supply of the NAD precursors tryptophan and vitamin B3 in the diet was restricted during pregnancy."

Shows maternal precursor restriction alone reproduces the malformation spectrum, establishing this as an independent input.

Embryonic NAD Deficiency

Embryonic NAD falls below the level required to sustain the several hundred NAD-dependent reactions on which proliferating embryonic tissue depends. This is the convergence point of the disorder: genotype and maternal nutrition are two routes to the same deficit, and it is the deficit, not the variant, that determines outcome. In mice, defect type tracks the timing of the deficit during organogenesis; whether that also explains the variability between human patients, including siblings who share a genotype, has not been shown.

NAD+ biosynthetic process GO:0009435 ↓ DECREASED

Animal models

Haao-null mouse Mouse recapitulates Reproduces both the NAD deficit and the resulting multi-organ malformation pattern seen in patients with the orthologous lesion.

Haao-null mouse Mouse rescues Gestational niacin supplementation in the null mother prevents the malformations, which is the rescue arm establishing that the NAD deficit is the operative lesion.

Kynu-null mouse Mouse recapitulates Confirms that the phenotype follows the pathway block rather than a gene-specific moonlighting function, since two different enzymatic steps give the same result.

ATDA-treated zebrafish Zebrafish partially recapitulates Reproduces cardiac and craniofacial anomalies and their nicotinamide rescue, but through a teratogen rather than a lesion in a CNDD gene.

Downstream

Impaired Somitogenesis

Disrupted Cardiac Morphogenesis

Disrupted Nephrogenesis

Disrupted Limb Morphogenesis

Embryonic Growth Restriction

Show evidence (2 references)

PMID:28792876 SUPPORT Model Organism

"Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency."

Establishes NAD deficiency, rather than another consequence of the gene lesion, as the proximate cause of the malformations.

PMID:41630685 SUPPORT Model Organism

"Variability in the timing of maternal metabolic perturbation corresponded to variability in organ and tissue defect types between litters."

Supports the claim that defect type follows the timing of the NAD deficit.

Impaired Somitogenesis

Vertebrae and ribs form from somites budding sequentially off the presomitic mesoderm during weeks 4 to 6 of human gestation. NAD deficiency during this window perturbs segmentation, producing the hemivertebrae, vertebral fusions and rib anomalies characteristic of the disorder. The lesion is in the metabolic substrate the forming somites depend on rather than in the segmentation clock itself.

somitogenesis GO:0001756 ⚠ ABNORMAL

Downstream

Vertebral segmentation defects

Rib anomalies

Hemivertebrae

Vertebral fusion

Show evidence (1 reference)

PMID:34681008 SUPPORT Other

"In human embryogenesis, the vertebral column develops at 4–6 weeks of gestation from the paraxial mesoderm (PSM) and is closely related to the spinal cord and other organs originating from mesoderm"

Background from the paper's introduction rather than a study finding. Establishes the developmental window and tissue of origin in which the NAD deficit acts on the axial skeleton.

Disrupted Cardiac Morphogenesis

NAD deficiency during cardiac looping and septation produces structural heart disease. Lesions are not confined to one side of the heart, and range from mild aortic arch abnormalities to hypoplastic left heart.

heart development GO:0007507 ⚠ ABNORMAL

Downstream

Congenital heart defect

Hypoplastic left heart syndrome

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Congenital heart defects can include left-sided heart lesions, right-sided heart lesions, or both."

Documents the non-lateralized distribution of cardiac lesions.

Disrupted Nephrogenesis

NAD deficiency during ureteric bud outgrowth and metanephric induction produces renal maldevelopment spanning hypoplasia and dysplasia through to complete bilateral agenesis, which is lethal.

kidney development GO:0001822 ⚠ ABNORMAL

Downstream

Renal agenesis

Renal hypoplasia or dysplasia

Show evidence (1 reference)

PMID:31883644 SUPPORT Human Clinical

"Defects range from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney"

Documents the renal severity range, including isolated bilateral renal agenesis as a presentation.

Disrupted Limb Morphogenesis

NAD deficiency during limb bud outgrowth and patterning produces limb reduction defects and disproportionate limb shortening that persists as short-limb short stature in survivors.

limb development GO:0060173 ⚠ ABNORMAL

Downstream

Limb anomalies

Short stature with disproportionately short limbs

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Almost all surviving individuals have short stature, many with disproportionately shortened limbs."

Documents the limb phenotype in survivors.

Embryonic Growth Restriction

Below a threshold of NAD availability the conceptus does not survive. Miscarriage is common in affected families and is part of the phenotypic spectrum rather than an unrelated obstetric event, so it belongs in the recurrence-risk conversation.

Downstream

Pregnancy loss

Show evidence (1 reference)

PMID:40689776 SUPPORT Model Organism

"Congenital NAD deficiency disorder (CNDD) is an example of such recurrent malformations with variable expressivity, and miscarriages are also frequent among affected families"

Places pregnancy loss within the disorder's spectrum.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

31

Cardiovascular 3

Congenital heart defect FREQUENT Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:37499065 SUPPORT Human Clinical

"Congenital NAD deficiency disorder (CNDD) is a multisystem condition in which cardiac, renal, vertebral, and limb anomalies are common, mimicking the clinical features described in VACTERL association."

Establishes cardiac involvement as one of the defining organ systems.

PMID:38357931 SUPPORT Human Clinical

"with heart defects, for example, ranging from relatively mild abnormalities of the aortic arch to life-threatening hypoplastic left heart"

Documents the severity range within the cardiac phenotype, which is why this entry binds the general term rather than a specific lesion.

Hypoplastic left heart syndrome Hypoplastic left ventricle HP:0004383

Show evidence (1 reference)

PMID:35491967 SUPPORT Human Clinical

"one patient had hypoplastic left heart syndrome (HLHS) and one had an aortic coarctation and transverse hypoplasia of the aortic arch, suggesting that NADSYN1 sequencing should be performed in children presenting with congenital anomalies"

Reports hypoplastic left heart in an individual with biallelic NADSYN1 variants.

Polysplenia OCCASIONAL HP:0001748

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"tracheoesophageal fistula, polysplenia, anteriorly displaced anus"

Lists polysplenia among the less common features.

Digestive 3

Tracheoesophageal fistula OCCASIONAL HP:0002575

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"sensorineural hearing loss, tracheoesophageal fistula, polysplenia"

Lists tracheoesophageal fistula among the less common features.

Anteriorly displaced anus OCCASIONAL Anteriorly placed anus HP:0001545

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"polysplenia, anteriorly displaced anus, tethered spinal cord"

Lists anteriorly displaced anus among the less common features.

Pyloric stenosis OCCASIONAL HP:0002021

Show evidence (1 reference)

PMID:37499065 SUPPORT INDIRECT Human Clinical

"tracheoesophageal fistula / pyloric stenosis / laryngeal web"

GeneReviews lists pyloric stenosis among the anomalies requiring standard treatment, which implies it occurs in this disorder.

Ear 1

Sensorineural hearing loss OCCASIONAL Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"eye anomalies, sensorineural hearing loss, tracheoesophageal fistula"

Lists sensorineural hearing loss among the less common features.

Endocrine 2

Hypothyroidism OCCASIONAL HP:0000821

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Other less common features may include cleft palate, eye anomalies, sensorineural hearing loss, tracheoesophageal fistula, polysplenia, anteriorly displaced anus, tethered spinal cord, cystic hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."

Lists hypothyroidism among the less common features.

Hypoparathyroidism OCCASIONAL HP:0000829

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Other less common features may include cleft palate, eye anomalies, sensorineural hearing loss, tracheoesophageal fistula, polysplenia, anteriorly displaced anus, tethered spinal cord, cystic hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."

Lists hypoparathyroidism among the less common features.

Eye 3

Eye anomalies OCCASIONAL Abnormality of the eye HP:0000478

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Other less common features may include cleft palate, eye anomalies, sensorineural hearing loss"

Lists eye anomalies among the less common features.

Ptosis OCCASIONAL HP:0000508

Show evidence (2 references)

PMID:37499065 SUPPORT INDIRECT Human Clinical

"Supportive care includes standard treatment for congenital anomalies (congenital heart defects, cleft palate, limb anomalies, scoliosis, tethered spinal cord, renal anomalies, tracheoesophageal fistula / pyloric stenosis / laryngeal web, polysplenia, and strabismus/ptosis)"

GeneReviews lists ptosis among the anomalies requiring standard treatment, which implies it occurs in this disorder rather than stating the phenotype directly.

PMID:36649848 SUPPORT Human Clinical

"unequal leg length as well as bilateral ptosis, cleft palate and asymmetric dysmorphic facial features"

Reports bilateral ptosis in a genetically confirmed affected individual.

Strabismus OCCASIONAL HP:0000486

Show evidence (1 reference)

PMID:37499065 SUPPORT INDIRECT Human Clinical

"tracheoesophageal fistula / pyloric stenosis / laryngeal web, polysplenia, and strabismus/ptosis"

GeneReviews lists strabismus among the anomalies requiring standard treatment, which implies it occurs in this disorder.

Genitourinary 2

Renal agenesis HP:0000104

Not evenly distributed across subtypes. In the largest genotyped NADSYN1 series the kidneys were the least frequently affected of the four cardinal systems (3 of 12), and the reported adult with NADSYN1-associated disease had no renal or urinary tract malformation at all, so a normal renal ultrasound does not argue against the diagnosis.

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Renal anomalies may be severe, including dysplasia/hypoplasia and renal agenesis."

Names renal agenesis among the documented renal lesions.

Renal hypoplasia or dysplasia Renal dysplasia HP:0000110

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Renal anomalies may be severe, including dysplasia/hypoplasia"

Names dysplasia and hypoplasia as documented renal lesions.

Head and Neck 4

Cleft palate OCCASIONAL HP:0000175

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Other less common features may include cleft palate, eye anomalies, sensorineural hearing loss, tracheoesophageal fistula, polysplenia, anteriorly displaced anus, tethered spinal cord, cystic hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."

GeneReviews lists cleft palate among the less common features.

Cystic hygroma OCCASIONAL HP:0000476

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"tethered spinal cord, cystic hygroma, epilepsy"

Lists cystic hygroma among the less common features.

Facial dysmorphism FREQUENT Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:38357931 SUPPORT Human Clinical

"mild facial dysmorphism (7 of 12) and craniofacial (6 of 12), growth (5 of 12), neurodevelopmental (4 of 12), and central nervous system (3 of 12) abnormalities"

Gives the observed frequency of facial dysmorphism in a genotyped CNDD series.

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:38357931 SUPPORT Human Clinical

"F7.II.3 had shown developmental progress to a level consistent with age, but remained microcephalic with mild improvement in growth parameters"

Documents microcephaly in a genotyped individual, and that it did not resolve on supplementation.

Immune 1

Pellagra-like dermatitis Inflammatory abnormality of the skin HP:0011123

Show evidence (1 reference)

PMID:38357931 SUPPORT Human Clinical

"Both siblings, however, experienced previously unseen life-threatening episodes of pellagra-like dermatitis, a characteristic postnatal consequence of NAD deficiency (15) that has not been reported previously in NADSYN1 deficiency."

First report of this manifestation in NADSYN1 deficiency.

Limbs 1

Limb anomalies FREQUENT Abnormal limb bone morphology HP:0002813

Show evidence (2 references)

PMID:38357931 SUPPORT Human Clinical

"Congenital abnormalities mostly affected the vertebrae (10 of 12), heart (9 of 12), and limbs (8 of 12) while less frequently affecting the kidneys (3 of 12)."

Quantifies limb involvement in a genotyped CNDD series and places it above renal involvement in that cohort.

PMID:37499065 SUPPORT Human Clinical

"cardiac, renal, vertebral, and limb anomalies are common"

GeneReviews names limb anomalies among the common features.

Musculoskeletal 5

Vertebral segmentation defects FREQUENT HP:0003422

Sequelae: Scoliosis

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Vertebral anomalies, including hemivertebrae and vertebral fusion, occur frequently, often with rib anomalies."

GeneReviews documents the specific vertebral lesions and their frequency.

Hemivertebrae HP:0002937

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Vertebral anomalies, including hemivertebrae and vertebral fusion, occur frequently"

Names hemivertebrae as a documented lesion.

Vertebral fusion HP:0002948

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"including hemivertebrae and vertebral fusion, occur frequently"

Names vertebral fusion as a documented lesion.

Rib anomalies Abnormal rib morphology HP:0000772

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"occur frequently, often with rib anomalies"

Documents co-occurring rib involvement.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:37499065 SUPPORT INDIRECT Human Clinical

"At each visit until skeletal maturity: monitoring for scoliosis."

Scoliosis is monitored to skeletal maturity, which implies it is expected. The quote states the surveillance, not the phenotype.

Nervous System 3

Developmental delay or intellectual disability FREQUENT Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Developmental delay / intellectual disability has been reported in more than half of affected individuals, although some affected individuals have had normal development, and some individuals succumbed to their congenital anomalies before developmental assessment could be performed."

States the frequency and the ascertainment caveat behind it.

Tethered spinal cord OCCASIONAL Tethered cord HP:0002144

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"anteriorly displaced anus, tethered spinal cord, cystic hygroma"

Lists tethered spinal cord among the less common features.

Epilepsy OCCASIONAL Seizure HP:0001250

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Other less common features may include cleft palate, eye anomalies, sensorineural hearing loss, tracheoesophageal fistula, polysplenia, anteriorly displaced anus, tethered spinal cord, cystic hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."

Lists epilepsy among the less common features.

Respiratory 1

Laryngeal web OCCASIONAL HP:0005950

Show evidence (1 reference)

PMID:37499065 SUPPORT INDIRECT Human Clinical

"pyloric stenosis / laryngeal web, polysplenia"

GeneReviews lists laryngeal web among the anomalies requiring standard treatment, which implies it occurs in this disorder.

Growth 1

Short stature with disproportionately short limbs VERY_FREQUENT Disproportionate short-limb short stature HP:0008873

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"Almost all surviving individuals have short stature, many with disproportionately shortened limbs."

Gives both the manifestation and its near-universal frequency among survivors.

Other 1

Pregnancy loss

Left unbound. HPO codes this concept under Pregnancy history (HP:0200067, Recurrent spontaneous abortion) and Prenatal death (HP:0034241), neither of which is reachable from the Phenotypic abnormality root that the PhenotypeTerm enum expands from, so no valid binding exists. Recorded as free text rather than forced onto a term that means something else.

Show evidence (2 references)

PMID:32015132 SUPPORT Model Organism

"Biallelic loss-of-function variants in HAAO or KYNU, two genes of the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are causative of congenital malformation and miscarriage in humans and mice."

States that the same lesions cause miscarriage as well as malformation. The sentence names humans, but it is the framing of a mouse study, so it is graded for the publication it comes from.

PMID:41170824 SUPPORT INDIRECT Human Clinical

"Women with a history of recurrent miscarriage have higher blood, plasma, and urine concentrations of NAD Salvage Pathway excretion products, and urinary excretion of nicotinamide (NAM) is also elevated, compared to control women."

Human evidence linking NAD metabolism to recurrent miscarriage. It is a study of women with recurrent miscarriage generally, not a CNDD cohort, so it supports the connection without establishing it in this disorder.

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Genetic Associations

3

HAAO

Gene: HAAO hgnc:4796 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:28792876 SUPPORT In Vitro

"The mutant enzymes had greatly reduced activity in vitro."

Functional assay confirms the variants are loss-of-function rather than merely rare.

PMID:33942433 SUPPORT In Vitro

"For the first time, missense mutations are identified as a cause of malformation and shown to disrupt enzyme function."

Extends the allelic spectrum beyond truncating variants.

KYNU

Gene: KYNU hgnc:6469 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:34200361 SUPPORT Human Clinical

"High-resolution SNP array analysis subsequently delineated a maternal isodisomy of chromosome 2 (UPD2)."

Documents uniparental isodisomy as a route to biallelic KYNU loss.

NADSYN1

Gene: NADSYN1 hgnc:29832 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:38357931 SUPPORT In Vitro

"Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico."

Characterizes how NADSYN1 variants impair the enzyme.

PMID:38357931 SUPPORT Human Clinical

"Phenotypes vary between CNDD patients (9) and do not appear proportional to the enzymatic activity of their respective protein variants."

Supports the claim that residual activity does not predict severity.

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Medical Actions

4

Antenatal NAD precursor supplementation

Action: nutritional supplementation with an NAD precursor Ontology label: Nutritional Support NCIT:C15433

Agent: nicotinic acid CHEBI:15940 nicotinamide CHEBI:17154 nicotinamide mononucleotide CHEBI:50383

Platform: Small molecule

Vitamin B3 supplementation before and during a subsequent at-risk pregnancy is the only intervention that addresses the mechanism rather than its consequences, and it is preventive rather than curative: it must be in place during organogenesis, which is largely complete before most affected pregnancies are recognized. The prevention evidence is from mouse models; no human trial has shown prevention of CNDD in an at-risk pregnancy, so this is a mechanistically motivated recommendation, not a proven one. The choice of vitamer is likewise a mouse result: in Nadsyn1-null mice nicotinic acid was not sufficient and amidated precursors were required, and that has not been tested in humans.

Mechanism Target:

RESTORES Embryonic NAD Deficiency — Raises the maternal precursor pool so that embryonic NAD stays above the organogenesis threshold.

Show evidence (1 reference)

PMID:28792876 SUPPORT Model Organism

"In null mice, the prevention of NAD deficiency during gestation averted defects."

Shows the intervention acts by correcting this specific mechanism node.

Show evidence (2 references)

PMID:38357931 SUPPORT Model Organism

"We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes."

Describes the supplementation strategy this treatment records.

PMID:38357931 SUPPORT Human Clinical

"Additional clinical trials are needed before accurate dosage recommendations required to prevent CNDD-dependent malformation can be made."

Establishes that the human dosing question is open, which is why this treatment is described as mechanistically motivated rather than established.

Postnatal amidated NAD precursor supplementation

Action: nutritional supplementation with an amidated NAD precursor Ontology label: Nutritional Support NCIT:C15433

Agent: nicotinamide CHEBI:17154

Platform: Small molecule

Distinct from the antenatal preventive use: metabolome data suggest affected individuals continue to have inadequate NAD after birth, so maintaining NAD with amidated precursors may be warranted beyond the prenatal window. The concrete indication is postnatal NAD-dependent disease rather than the fixed malformations, which supplementation cannot undo: nicotinamide prevented recurrent life-threatening pellagra-like dermatitis in two NADSYN1-null siblings, and raised blood NAD in genotyped individuals. Beyond that it is a suggestion from the metabolome study, not established practice; GeneReviews records no cure and describes management as supportive.

Show evidence (6 references)

PMID:38357931 SUPPORT Human Clinical

"suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth"

States the postnatal supplementation rationale, and its hedged framing is why this entry does not present it as established.

PMID:38357931 SUPPORT INDIRECT Human Clinical

"A 1-month-old individual with CNDD caused by biallelic loss-of-function HAAO variants was reported to have improved in length and development after 3 months of NA supplementation"

A single reported human response to postnatal supplementation. Note the precursor here is nicotinic acid, not an amidated one, and the subtype is HAAO, where the Preiss-Handler route is intact; it therefore supports postnatal supplementation in general rather than the amidated requirement this treatment is named for.

PMID:38357931 SUPPORT Human Clinical

"F7.II.3 at 100 mg/d for 6 weeks, who exhibited a 115% increase in blood NAD levels in comparison with unsupplemented conditions"

The amidated-precursor human data proper, showing nicotinamide raised blood NAD in a genotyped individual.

+ 3 more references

Supportive management of congenital anomalies

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

There is no cure. Management is standard treatment of each malformation and of the functional consequences, coordinated across cardiology, nephrology, orthopaedics, ENT, ophthalmology and developmental services, with structured surveillance for scoliosis, hearing, vision, thyroid function, calcium and renal function. Medications that impair kidney function should be avoided in those with a solitary kidney or known renal impairment.

Target Phenotypes: Abnormal heart morphology HP:0001627 Scoliosis HP:0002650 Renal dysplasia HP:0000110 Cleft palate HP:0000175 Tethered cord HP:0002144

Show evidence (2 references)

PMID:37499065 SUPPORT Human Clinical

"There is no cure for CNDD."

Establishes that management is supportive rather than curative.

PMID:37499065 SUPPORT Human Clinical

"Agents/circumstances to avoid: Avoidance of medications that impair kidney function, in those with renal aplasia (solitary kidney) and/or known impaired kidney function."

Records the GeneReviews drug-safety warning reflected in this treatment's description.

Genetic counselling and family evaluation

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Autosomal recessive recurrence risk is 25% per pregnancy. Because malformations can be occult, at-risk relatives should be evaluated once the familial variants are known. Uniparental isodisomy has been documented as a route to biallelic KYNU loss, which changes the recurrence risk for that family and is a reason to establish the mechanism rather than assume biparental inheritance.

Show evidence (3 references)

PMID:37499065 SUPPORT Human Clinical

"It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from more in-depth evaluation for occult congenital malformations."

Records the recommendation to evaluate at-risk relatives.

PMID:37499065 SUPPORT Human Clinical

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

The recurrence risk figures this entry cites elsewhere.

PMID:37499065 SUPPORT Human Clinical

"carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible."

Records the reproductive testing options available once the familial variants are known.

🌍

Environmental Factors

2

Maternal dietary NAD precursor insufficiency during pregnancy

Low maternal intake of tryptophan and vitamin B3 lowers the NAD precursor supply reaching the conceptus. In mice this alone causes the malformation spectrum in genetically normal embryos, and combined with a single heterozygous pathway allele it produces a markedly worse outcome than either factor separately.

Show evidence (2 references)

PMID:32015132 SUPPORT Model Organism

"Our data show that NAD deficiency as a cause of embryo loss and congenital malformation is not restricted to the rare cases of biallelic mutations in NAD synthesis pathway genes."

Supports treating maternal dietary insufficiency as an independent environmental cause.

PMID:34748060 SUPPORT INDIRECT Human Clinical

"The meta-analysis showed that expectant mothers with an insufficient niacin intake were significantly more likely to have babies with congenital abnormalities (odds ratio 1.13, 95% confidence interval 1.02-1.24) compared to mothers with adequate niacin intake."

The human counterpart to the mouse dietary experiments. It is a population-level association across all congenital anomalies, not a CNDD cohort, so it supports the exposure being consequential in humans without establishing this mechanism in any individual pregnancy.

Mechanism Target:

TRIGGERS Insufficient Maternal NAD Precursor Provision — Dietary restriction of both NAD precursors is the exposure that establishes inadequate maternal provision.

Show evidence (1 reference)

PMID:32015132 SUPPORT Model Organism

"When the dietary undersupply was combined with a maternal heterozygous variant in Haao, which alone does not cause NAD deficiency or malformations, the incidence of embryo loss and malformations was significantly higher, suggesting a gene-environment interaction."

Establishes the exposure acting on maternal NAD provision and its interaction with genotype.

Gestational niacin supplementation

Vitamin B3 supplementation during pregnancy raises maternal and embryonic NAD and prevents the malformations in mouse models. The choice of vitamer matters and depends on where the block sits: nicotinic acid entering through the Preiss-Handler pathway still requires NADSYN1, so NADSYN1-null mothers need amidated precursors that bypass the terminal step.

Show evidence (2 references)

PMID:28792876 SUPPORT Model Organism

"Niacin supplementation during gestation prevented the malformations in mice."

Establishes the protective effect of the exposure.

PMID:38357931 SUPPORT Model Organism

"While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block."

Supports the claim that vitamer choice depends on the position of the enzymatic block.

Mechanism Target:

PROTECTS_AGAINST Embryonic NAD Deficiency — Supplementation restores the precursor supply and prevents the NAD deficit that drives the malformations.

Show evidence (1 reference)

PMID:28792876 SUPPORT Model Organism

"In null mice, the prevention of NAD deficiency during gestation averted defects."

Demonstrates that correcting the NAD deficit prevents the downstream malformations.

🔬

Biochemical Markers

3

Decreased circulating NAD (PRESENT)

Show evidence (2 references)

PMID:28792876 SUPPORT Human Clinical

"The patients had reduced levels of circulating NAD."

Directly documents the biochemical abnormality in affected individuals.

PMID:36951206 SUPPORT Human Clinical

"Decreased plasmatic levels of NAD should then strongly encourage the screening for any of the genes responsible for a NAD deficiency disorder."

Supports the diagnostic role of the measurement.

Elevated circulating 3-hydroxyanthranilic acid

Context: The substrate immediately upstream of HAAO, predicted to accumulate when 3-hydroxyanthranilate 3,4-dioxygenase activity is lost.

Show evidence (1 reference)

PMID:28792876 SUPPORT INDIRECT Human Clinical

"We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma."

Establishes only that plasma kynurenine-pathway metabolites were measured in these patients. It names neither this analyte nor a direction, which is why this record is marked predicted, not observed.

Elevated urinary xanthurenic acid (PRESENT)

Show evidence (1 reference)

PMID:34200361 SUPPORT Human Clinical

"Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis."

Reports the urinary finding and its diagnostic use in KYNU deficiency.

🔬

Diagnosis

2

Molecular genetic testing of HAAO, KYNU and NADSYN1

The diagnostic criterion. Exome, genome or a targeted panel covering the three pathway genes establishes the diagnosis in a proband with suggestive findings. Copy-number analysis matters as well as sequencing, since a homozygous exon deletion and a uniparental isodisomy have each produced biallelic loss in reported cases.

Show evidence (2 references)

PMID:37499065 SUPPORT Human Clinical

"The diagnosis of CNDD is established in a proband with suggestive findings and biallelic pathogenic variants in HAAO, KYNU, or NADSYN1 identified by molecular genetic testing."

States the diagnostic criterion.

PMID:34200361 SUPPORT Human Clinical

"Using Trio-Exome analysis and CGH array analysis in combination with long range PCR, we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU"

Shows that sequencing alone can miss the causal lesion, which is why copy-number analysis belongs in the workup.

Circulating NAD metabolome signature

Plasma NAD and kynurenine-pathway metabolite profiling identifies affected individuals and, because the accumulating species depends on which enzyme is lost, points to the gene to sequence. GeneReviews establishes the diagnosis on biallelic pathogenic variants in HAAO, KYNU or NADSYN1; the metabolome is the finding that prompts that testing.

Show evidence (2 references)

PMID:37499065 SUPPORT Human Clinical

"The diagnosis of CNDD is established in a proband with suggestive findings and biallelic pathogenic variants in HAAO, KYNU, or NADSYN1 identified by molecular genetic testing."

States the diagnostic criterion.

PMID:38357931 SUPPORT Human Clinical

"Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD"

Supports the metabolome's diagnostic contribution.

📊

Prevalence

1

Worldwide, individuals with biallelic NADSYN1 variants

Cases In Literature Ultra Rare VCRL3

Case counts, not a population rate. Ascertainment is by case report and GeneMatcher rather than screening, so the published count is a floor on incidence and says nothing about how many affected pregnancies are lost before diagnosis or recorded as VACTERL association.

Show evidence (2 references)

PMID:38357931 SUPPORT Human Clinical

"To date, 11 individuals have been reported with CNDD caused by biallelic NADSYN1 variants (7, 11–13), the majority of whom have not survived past 3 months of age due to the severity of their malformations."

Gives the published case count for the NADSYN1 subtype at that point, together with its mortality.

PMID:36951206 SUPPORT Human Clinical

"Sixteen NADSYN1-associated patients have been published so far."

An independent count from the same period, consistent in order of magnitude.

⚖️

Clinical Burden

High

In the reported cohorts most affected individuals died in infancy of their malformations. Survivors carry lifelong consequences across several organ systems: short stature, developmental delay, and the surgical and surveillance burden of congenital heart disease, renal maldevelopment and progressive scoliosis. The burden also falls on the family through recurrent pregnancy loss and a 25% recurrence risk.

Show evidence (1 reference)

PMID:38357931 SUPPORT Human Clinical

"the majority of whom have not survived past 3 months of age due to the severity of their malformations"

Documents the mortality that drives the burden assessment.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Congenital Vertebral-Cardiac-Renal Anomalies Syndrome:

VACTERL association

Overlapping Features CNDD is clinically indistinguishable from VACTERL association in many individuals, and the overlap is the main reason the disorder is underdiagnosed. The practical separator is that CNDD has a testable biochemical and molecular basis, so a VACTERL-like presentation is a reason to measure NAD rather than to stop at a descriptive label.

Show evidence (1 reference)

PMID:37499065 SUPPORT Human Clinical

"cardiac, renal, vertebral, and limb anomalies are common, mimicking the clinical features described in VACTERL association"

States the phenotypic overlap that drives the differential.

Catel-Manzke syndrome

Overlapping Features A KYNU-deficient individual has been reported with features overlapping both VCRL and Catel-Manzke syndrome, so the two can present together.

Show evidence (1 reference)

PMID:34200361 SUPPORT Human Clinical

"in an individual presenting with overlapping features of VCRL and Catel-Manzke Syndrome"

Documents the reported overlap.

Hydroxykynureninuria without malformation

Overlapping Features KYNU variants that leave residual kynureninase activity produce the biochemical picture of this disorder, hydroxykynureninuria with xanthurenic aciduria, in individuals who have no congenital malformations. It is the same gene and the same metabolic block, separated only by how much enzyme is left, which is why a raised xanthurenic acid alone does not establish CNDD. The cited review does not report the zygosity of the reported brothers' variant, so this entry does not assert it; the mechanistic claim it does make is about residual enzyme activity, not about allele configuration.

Show evidence (2 references)

PMID:34200361 SUPPORT Human Clinical

"Christensen et al. described two brothers with a missense variant in KYNU, resulting in a threonine to alanine amoinoacid exchange (p.Thr198Ala), presenting with hydroxykynureninuria and xanthurenic aciduria but without congenital malformations"

Documents the allelic condition and that it lacks the malformations that define CNDD.

PMID:34200361 SUPPORT Human Clinical

"A residual activity of kynureninase in these patients with consequently higher levels of plasma NAD+ could explain the distinct phenotype"

Gives the proposed basis for the split, residual activity keeping NAD above the threshold organogenesis needs.

Congenital vertebral malformation of other genetic cause

Overlapping Features In a cohort ascertained for congenital vertebral malformation, rare NADSYN1 variants were recovered in a minority of patients, though as heterozygous variants of uncertain significance rather than the biallelic loss that defines CNDD. Most congenital vertebral malformation is not CNDD, and the segmentation-clock disorders remain the larger differential.

Show evidence (1 reference)

PMID:34681008 SUPPORT Human Clinical

"Our findings demonstrated that functional variants in NADSYN1 were involved in the complex genetic etiology of CVMs"

Places CNDD as one contributor among several to congenital vertebral malformation.

🐁

Animal Models

5

Haao-null mouse Genetic

CRISPR-Cas9 engineered null mouse that develops the human malformation spectrum when maternal NAD precursor supply is limited, and is protected by gestational niacin.

Species

Mouse

Genotype

Haao-/-

Genes

HAAO hgnc:4796

Publication

PMID:28792876

Pathograph links

Embryonic NAD Deficiency recapitulates fidelity: high Reproduces both the NAD deficit and the resulting multi-organ malformation pattern seen in patients with the orthologous lesion.

Limitations: Penetrance depends on the maternal diet used, so a result from this model is conditional on the dietary regimen and cannot be read as an unqualified genotype-phenotype statement.

Readouts

Embryonic NAD level

Direction: DECREASED

Interpretation: Direct measurement of the deficit this node describes.

Show evidence (1 reference)

PMID:40689776 SUPPORT Model Organism

"mouse embryos with genetic disruption of NAD de novo synthesis (Haao-/-) were more susceptible to CNDD when maternal circulatory nicotinamide was limited, as their yolk sacs cannot generate NAD de novo from tryptophan"

Reports the embryonic NAD vulnerability measured in this genotype.

Show evidence (1 reference)

PMID:28792876 SUPPORT Model Organism

"Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency."

Supports treating this model as informative for the NAD deficiency node.

Embryonic NAD Deficiency rescues fidelity: high Gestational niacin supplementation in the null mother prevents the malformations, which is the rescue arm establishing that the NAD deficit is the operative lesion.

Show evidence (1 reference)

PMID:28792876 SUPPORT Model Organism

"Niacin supplementation during gestation prevented the malformations in mice."

Documents the rescue.

Show evidence (1 reference)

PMID:28792876 SUPPORT Model Organism

"We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system."

Describes how this model was constructed, establishing that it carries the orthologous lesion rather than an unrelated null allele.

Kynu-null mouse Genetic

Null mouse for the kynureninase step, developing the same malformation spectrum as the Haao-null model.

Species

Mouse

Genotype

Kynu-/-

Genes

KYNU hgnc:6469

Publication

PMID:28792876

Pathograph links

Embryonic NAD Deficiency recapitulates fidelity: high Confirms that the phenotype follows the pathway block rather than a gene-specific moonlighting function, since two different enzymatic steps give the same result.

Limitations: As with the Haao model, expression of the phenotype is conditional on the maternal dietary NAD precursor regimen.

Show evidence (1 reference)

PMID:28792876 SUPPORT Model Organism

"Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency."

Supports this model as informative for the NAD deficiency node.

Show evidence (1 reference)

PMID:28792876 SUPPORT Model Organism

"Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency."

Reports the malformation phenotype in this genotype.

Nadsyn1-null mouse Genetic

Model of the terminal-step block, used to work out which B3 vitamer can rescue a given genotype.

Species

Mouse

Genotype

Nadsyn1-/-

Genes

NADSYN1 hgnc:29832

Publication

PMID:38357931

Pathograph links

De Novo NAD Synthesis Pathway Enzymatic Block recapitulates fidelity: high Reproduces NADSYN1-dependent CNDD and shows that the position of the block determines which precursors can bypass it.

Limitations: The vitamer-specificity result is a mouse finding; the corresponding human supplementation strategy has not been tested in a trial.

Show evidence (1 reference)

PMID:38357931 SUPPORT Model Organism

"We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes."

Supports this model as informative for the enzymatic block node.

Show evidence (1 reference)

PMID:38357931 SUPPORT Model Organism

"We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes."

Establishes that this model reproduces the disorder, which is the basis for treating it as informative here.

Slc6a19 heterozygous mouse Genetic

Not a pathway-enzyme model. Heterozygous loss of the neutral amino acid transporter limits maternal tryptophan availability, showing that a gene outside NAD synthesis can produce the same disorder.

Species

Mouse

Genotype

Slc6a19+/-

Publication

PMID:36374036

Pathograph links

Insufficient Maternal NAD Precursor Provision recapitulates fidelity: moderate Models the maternal-supply arm rather than the embryonic enzymatic block, producing CNDD malformations through restricted tryptophan transport.

Limitations: Requires a vitamin B3-depleted maternal diet to manifest, and no human SLC6A19 carrier has been reported with this outcome, so the human relevance is inferred rather than demonstrated.

Show evidence (1 reference)

PMID:36374036 SUPPORT Model Organism

"Our results show that genes not directly involved in NAD synthesis can affect NAD metabolism and cause CNDD."

Supports this model as informative for the maternal provision node.

Show evidence (1 reference)

PMID:36374036 SUPPORT Model Organism

"Pregnant Slc6a19+/- mice were fed diets depleted of vitamin B3, so that tryptophan was the source of NAD during gestation."

Describes the model and the dietary condition it requires, which is the basis for treating it as informative here.

ATDA-treated zebrafish Chemical

A chemically induced rather than genetic model, valuable because zebrafish embryos develop externally and can be watched in real time. Nicotinamide rescues the defects dose-dependently, which is the same rescue logic as the mouse models in a second vertebrate.

Species

Zebrafish

Genotype

Wild type treated with 2-amino-1,3,4-thiadiazole

Publication

PMID:39829932

Pathograph links

Embryonic NAD Deficiency partially recapitulates fidelity: moderate Reproduces cardiac and craniofacial anomalies and their nicotinamide rescue, but through a teratogen rather than a lesion in a CNDD gene.

Limitations: ATDA is a chemical inhibitor of NAD metabolism, not a model of biallelic HAAO/KYNU/NADSYN1 loss, so off-target effects cannot be excluded. The defect set is also zebrafish-specific: neural tube and tail defects rather than the vertebral, renal and limb malformations that define the human disorder.

Show evidence (1 reference)

PMID:39829932 SUPPORT Model Organism

"Treatment of zebrafish embryos with 2-amino-1,3,4-thiadiazole (ATDA), a teratogen known to disrupt NAD+ metabolism, resulted in neural tube, craniofacial, cardiac, and tail defects. These defects were rescued by the administration of nicotinamide (NAM) in a dose-dependent manner."

Reports both the phenotype and its NAD-precursor rescue, which is what makes this model informative for the NAD deficiency node.

Show evidence (1 reference)

PMID:39829932 SUPPORT Model Organism

"Here, we describe a zebrafish model of NAD+ disruption to begin to model CNDD and VACTERL association phenotypes, assessing developmental anomalies in real-time."

Establishes the model and what it is for.

{ }

Source YAML

click to show

name: Congenital Vertebral-Cardiac-Renal Anomalies Syndrome
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
description: >-
  An autosomal recessive multiple-malformation syndrome, also called congenital
  NAD deficiency disorder (CNDD), caused by biallelic loss-of-function variants
  in one of three non-redundant enzymes of the de novo nicotinamide adenine
  dinucleotide (NAD) synthesis pathway that converts L-tryptophan to NAD via
  kynurenine: HAAO (VCRL1), KYNU (VCRL2), and NADSYN1 (VCRL3). The enzymatic
  block lowers embryonic NAD below the level organogenesis requires, producing
  vertebral segmentation defects, congenital heart disease, renal anomalies and
  limb defects that mimic the VACTERL association, together with short stature,
  developmental delay and embryo loss. Because NAD can also be made from dietary
  vitamin B3, the severity of the disorder depends on maternal NAD precursor
  supply as well as genotype, and gestational niacin supplementation prevents the
  malformations in mouse models.
disease_term:
  preferred_term: congenital vertebral-cardiac-renal anomalies syndrome
  term:
    id: MONDO:0020831
    label: congenital vertebral-cardiac-renal anomalies syndrome
synonyms:
- congenital NAD deficiency disorder
- CNDD
- VCRL syndrome
- vertebral, cardiac, renal and limb defects syndrome
references:
- reference: PMID:37499065
  title: Congenital NAD Deficiency Disorder
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All three CNDD genocopies require biallelic loss-of-function variants.
    Heterozygous carriers are clinically unaffected under adequate dietary NAD
    precursor intake, but mouse data show that maternal heterozygosity combined
    with dietary vitamin B3 restriction is sufficient to cause malformations,
    so carrier status is not phenotypically inert under nutritional stress.
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CNDD is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the mode of inheritance for the disorder.
has_subtypes:
- name: VCRL1
  display_name: Vertebral, cardiac, renal, and limb defects syndrome 1 (HAAO)
  description: >-
    Caused by biallelic HAAO variants that abolish 3-hydroxyanthranilate
    3,4-dioxygenase, the enzyme converting 3-hydroxyanthranilic acid to the
    quinolinate precursor. The block sits several enzymatic steps upstream of
    NAD, and 3-hydroxyanthranilic acid is predicted to accumulate behind it.
  subtype_term:
    preferred_term: vertebral, cardiac, renal, and limb defects syndrome 1
    term:
      id: MONDO:0060554
      label: vertebral, cardiac, renal, and limb defects syndrome 1
  genes:
  - preferred_term: HAAO
    term:
      id: hgnc:4796
      label: HAAO
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients carried homozygous variants predicting loss-of-function
      changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU
      p.V57Efs*21)."
    explanation: The founding report identifies biallelic HAAO loss-of-function
      variants in affected individuals.
- name: VCRL2
  display_name: Vertebral, cardiac, renal, and limb defects syndrome 2 (KYNU)
  description: >-
    Caused by biallelic KYNU variants that abolish kynureninase, blocking
    conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. The
    accumulating 3-hydroxykynurenine is shunted to xanthurenic acid, which is
    excreted in urine and can be used diagnostically.
  subtype_term:
    preferred_term: vertebral, cardiac, renal, and limb defects syndrome 2
    term:
      id: MONDO:0060555
      label: vertebral, cardiac, renal, and limb defects syndrome 2
  genes:
  - preferred_term: KYNU
    term:
      id: hgnc:6469
      label: KYNU
  evidence:
  - reference: PMID:34200361
    reference_title: "A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified a novel homozygous copy number variant (CNV)
      encompassing exon 5 of KYNU in an individual presenting with overlapping
      features of VCRL and Catel-Manzke Syndrome"
    explanation: Documents a biallelic KYNU lesion producing the VCRL phenotype.
- name: VCRL3
  display_name: Vertebral, cardiac, renal, and limb defects syndrome 3 (NADSYN1)
  description: >-
    Caused by biallelic NADSYN1 variants that abolish NAD synthetase 1, the
    terminal step shared by the de novo and Preiss-Handler routes. Because the
    block is downstream of the point at which dietary nicotinic acid enters,
    nicotinic acid is predicted not to rescue a NADSYN1-null individual. That
    vitamer specificity was shown in Nadsyn1-null mice and has not been tested
    in humans. This is the most phenotypically variable subtype, spanning
    prenatal lethality to individuals with no malformation at all.
  subtype_term:
    preferred_term: vertebral, cardiac, renal, and limb defects syndrome 3
    term:
      id: MONDO:0030077
      label: vertebral, cardiac, renal, and limb defects syndrome 3
  genes:
  - preferred_term: NADSYN1
    term:
      id: hgnc:29832
      label: NADSYN1
  evidence:
  - reference: PMID:31883644
    reference_title: "Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present five individuals from four unrelated families,
      individuals who share similar phenotypes with disease-causal bi-allelic
      variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the
      nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway"
    explanation: Establishes NADSYN1 as the third CNDD gene.
  - reference: PMID:36951206
    reference_title: "Clinical heterogeneity of NADSYN1-associated VCRL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two of them being siblings with the same homozygous variant and
      presenting with either a very severe prenatal lethal or a mild phenotypic
      form"
    explanation: Documents the wide intrafamilial phenotypic variability that
      distinguishes the NADSYN1 subtype.
  - reference: PMID:36649848
    reference_title: "Adult patient diagnosed with NADSYN1 associated congenital
      NAD deficiency and analysis of NAD levels to be published in: European
      Journal of Medical Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a male patient age 30 with a height of 130 cm and
      numerous skeletal malformations including segmentation defects of the
      spine, rib anomalies and unequal leg length as well as bilateral ptosis,
      cleft palate and asymmetric dysmorphic facial features."
    explanation: Documents survival to adulthood in this subtype, against a
      literature otherwise dominated by infant deaths.
  - reference: PMID:36649848
    reference_title: "Adult patient diagnosed with NADSYN1 associated congenital
      NAD deficiency and analysis of NAD levels to be published in: European
      Journal of Medical Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No malformations of the kidneys or urinary tract were identified."
    explanation: Shows the renal arm of the four-organ pattern can be spared
      entirely, which is why a partial presentation should not exclude the
      diagnosis.
genetic:
- name: HAAO
  gene_term:
    preferred_term: HAAO
    term:
      id: hgnc:4796
      label: HAAO
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: VCRL1
  notes: >-
    Encodes 3-hydroxyanthranilate 3,4-dioxygenase. Both nonsense and missense
    alleles are pathogenic; missense variants were shown to be loss-of-function
    by yeast complementation rather than assumed to be so.
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutant enzymes had greatly reduced activity in vitro."
    explanation: Functional assay confirms the variants are loss-of-function
      rather than merely rare.
  - reference: PMID:33942433
    reference_title: "New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "For the first time, missense mutations are identified as a cause
      of malformation and shown to disrupt enzyme function."
    explanation: Extends the allelic spectrum beyond truncating variants.
- name: KYNU
  gene_term:
    preferred_term: KYNU
    term:
      id: hgnc:6469
      label: KYNU
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: VCRL2
  notes: >-
    Encodes kynureninase. Biallelic KYNU lesions have also arisen through
    uniparental isodisomy rather than biparental inheritance, which changes the
    recurrence risk counselling for the family.
  evidence:
  - reference: PMID:34200361
    reference_title: "A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-resolution SNP array analysis subsequently delineated a
      maternal isodisomy of chromosome 2 (UPD2)."
    explanation: Documents uniparental isodisomy as a route to biallelic KYNU
      loss.
- name: NADSYN1
  gene_term:
    preferred_term: NADSYN1
    term:
      id: hgnc:29832
      label: NADSYN1
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: VCRL3
  notes: >-
    Encodes NAD synthetase 1. Variant deleteriousness is domain-dependent, and
    the severity of the resulting phenotype does not track simply with residual
    enzyme activity.
  evidence:
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Enzymatic assessment of variant deleteriousness in vitro revealed
      protein domain-specific perturbation, complemented by protein structure
      modeling in silico."
    explanation: Characterizes how NADSYN1 variants impair the enzyme.
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypes vary between CNDD patients (9) and do not appear
      proportional to the enzymatic activity of their respective protein
      variants."
    explanation: Supports the claim that residual activity does not predict
      severity.
prevalence:
- population: Worldwide, individuals with biallelic NADSYN1 variants
  subtype: VCRL3
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Case counts, not a population rate. Ascertainment is by case report and
    GeneMatcher rather than screening, so the published count is a floor on
    incidence and says nothing about how many affected pregnancies are lost
    before diagnosis or recorded as VACTERL association.
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 11 individuals have been reported with CNDD caused by
      biallelic NADSYN1 variants (7, 11–13), the majority of whom have not
      survived past 3 months of age due to the severity of their malformations."
    explanation: Gives the published case count for the NADSYN1 subtype at that
      point, together with its mortality.
  - reference: PMID:36951206
    reference_title: Clinical heterogeneity of NADSYN1-associated VCRL syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixteen NADSYN1-associated patients have been published so far."
    explanation: An independent count from the same period, consistent in order
      of magnitude.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    In the reported cohorts most affected individuals died in infancy of their
    malformations. Survivors carry lifelong consequences across several organ
    systems: short stature, developmental delay, and the surgical and
    surveillance burden of congenital heart disease, renal maldevelopment and
    progressive scoliosis. The burden also falls on the family through recurrent
    pregnancy loss and a 25% recurrence risk.
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the majority of whom have not survived past 3 months of age due to
      the severity of their malformations"
    explanation: Documents the mortality that drives the burden assessment.
pathophysiology:
- name: De Novo NAD Synthesis Pathway Enzymatic Block
  description: >-
    Biallelic loss-of-function variants in HAAO, KYNU or NADSYN1 abolish one of
    three non-redundant enzymatic steps converting L-tryptophan to NAD through
    the kynurenine pathway. No parallel route bypasses the lost step within de
    novo synthesis, so flux through the pathway stops at the affected enzyme.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HAAO
    term:
      id: hgnc:4796
      label: HAAO
  - preferred_term: KYNU
    term:
      id: hgnc:6469
      label: KYNU
  - preferred_term: NADSYN1
    term:
      id: hgnc:29832
      label: NADSYN1
  molecular_functions:
  - preferred_term: 3-hydroxyanthranilate 3,4-dioxygenase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0000334
      label: 3-hydroxyanthranilate 3,4-dioxygenase activity
  - preferred_term: kynureninase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0030429
      label: kynureninase activity
  - preferred_term: NAD+ synthase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0008795
      label: NAD+ synthase activity
  biological_processes:
  - preferred_term: de novo NAD biosynthesis from L-tryptophan
    modifier: DECREASED
    term:
      id: GO:0034354
      label: "'de novo' NAD+ biosynthetic process from L-tryptophan"
  downstream:
  - target: Kynurenine Pathway Intermediate Accumulation
    causal_link_type: DIRECT
    description: Substrate immediately upstream of the lost enzyme accumulates.
  - target: Embryonic NAD Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nicotinamide adenine dinucleotide (NAD) is synthesized de novo
        from tryptophan through the kynurenine pathway. The patients had reduced
        levels of circulating NAD."
      explanation: Links the pathway lesion directly to measured NAD deficiency
        in affected individuals, not merely to the genotype.
  evidence:
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All CNDD cases identified to date originate from biallelic
      loss-of-function variants in any of 3 nonredundant genes of the NAD de
      novo synthesis pathway"
    explanation: States the shared molecular lesion and its non-redundancy.
- name: Kynurenine Pathway Intermediate Accumulation
  description: >-
    Metabolites immediately upstream of the enzymatic block accumulate and spill
    into plasma and urine. The identity of the accumulating species is
    gene-specific, which is what makes the circulating NAD metabolome
    diagnostically informative: HAAO loss raises 3-hydroxyanthranilic acid,
    KYNU loss raises 3-hydroxykynurenine and its transamination product
    xanthurenic acid, and NADSYN1 loss raises the terminal precursor
    deamido-NAD (nicotinate adenine dinucleotide).
  biological_scale: MOLECULAR
  chemical_entities:
  - preferred_term: 3-hydroxy-L-kynurenine
    term:
      id: CHEBI:17380
      label: 3-hydroxy-L-kynurenine
  - preferred_term: 3-hydroxyanthranilic acid
    term:
      id: CHEBI:15793
      label: 3-hydroxyanthranilic acid
  - preferred_term: deamido-NAD (nicotinate adenine dinucleotide)
    term:
      id: CHEBI:18304
      label: deamido-NAD(+)
  notes: >-
    No single biological_processes descriptor fits this node. Quinolinate
    biosynthesis is decreased in the HAAO and KYNU subtypes but not in VCRL3,
    where the NADSYN1 block sits downstream of quinolinate, so a process-level
    DECREASED tag scoped to the whole node would be wrong for a third of the
    disorder.
  evidence:
  - reference: PMID:34200361
    reference_title: "A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased xanthurenic acid excretion in the urine confirmed the
      genetic diagnosis."
    explanation: Demonstrates that the upstream intermediate accumulates
      measurably in a KYNU-deficient patient.
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The circulatory NAD metabolome in mice and humans before and after
      NAD precursor supplementation revealed a consistent metabolic signature
      with utility for patient identification."
    explanation: Supports the diagnostic use of the accumulated-metabolite
      pattern.
- name: Insufficient Maternal NAD Precursor Provision
  description: >-
    NAD available to the conceptus depends on maternal circulating tryptophan
    and vitamin B3 vitamers, which reach the embryo via the yolk sac before the
    embryonic liver is functional. Low maternal precursor supply lowers embryonic
    NAD independently of the embryo's own genotype, and is the environmental arm
    of the gene-environment interaction that sets phenotype severity.
  biological_scale: ORGANISM
  downstream:
  - target: Embryonic NAD Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40689776
      reference_title: "Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Maternal levels of nicotinamide positively correlated with
        embryonic NAD levels, highlighting its central role for embryonic NAD
        metabolism."
      explanation: Quantifies the maternal-supply-to-embryonic-NAD link that
        this edge asserts.
  evidence:
  - reference: PMID:32015132
    reference_title: "NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "C57BL/6J wild-type mice had offspring exhibiting similar
      malformations when their supply of the NAD precursors tryptophan and
      vitamin B3 in the diet was restricted during pregnancy."
    explanation: Shows maternal precursor restriction alone reproduces the
      malformation spectrum, establishing this as an independent input.
- name: Embryonic NAD Deficiency
  description: >-
    Embryonic NAD falls below the level required to sustain the several hundred
    NAD-dependent reactions on which proliferating embryonic tissue depends.
    This is the convergence point of the disorder: genotype and maternal
    nutrition are two routes to the same deficit, and it is the deficit, not the
    variant, that determines outcome. In mice, defect type tracks the timing of
    the deficit during organogenesis; whether that also explains the variability
    between human patients, including siblings who share a genotype, has not
    been shown.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: NAD+ biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0009435
      label: NAD+ biosynthetic process
  chemical_entities:
  - preferred_term: NAD+
    term:
      id: CHEBI:15846
      label: NAD(+)
  downstream:
  - target: Impaired Somitogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin
        Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defects similar to those in the patients developed in the
        embryos of Haao-null or Kynu-null mice owing to NAD deficiency."
      explanation: Attributes the organ malformations specifically to the NAD
        deficit, which is the causal step this edge asserts.
  - target: Disrupted Cardiac Morphogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin
        Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defects similar to those in the patients developed in the
        embryos of Haao-null or Kynu-null mice owing to NAD deficiency."
      explanation: Attributes the organ malformations specifically to the NAD
        deficit, which is the causal step this edge asserts.
  - target: Disrupted Nephrogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin
        Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defects similar to those in the patients developed in the
        embryos of Haao-null or Kynu-null mice owing to NAD deficiency."
      explanation: Attributes the organ malformations specifically to the NAD
        deficit, which is the causal step this edge asserts.
  - target: Disrupted Limb Morphogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin
        Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defects similar to those in the patients developed in the
        embryos of Haao-null or Kynu-null mice owing to NAD deficiency."
      explanation: Attributes the organ malformations specifically to the NAD
        deficit, which is the causal step this edge asserts.
  - target: Embryonic Growth Restriction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41630685
      reference_title: "Timing of NAD Deficiency During Organogenesis Dictates Defect Type and Penetrance."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice with lower maternal NAD Salvage Pathway metabolite levels
        and minimal levels of derived excretion metabolites from embryonic day
        6.5 onward had smaller embryos with more malformations."
      explanation: Directly ties the degree of NAD shortfall to reduced embryo
        size.
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Defects similar to those in the patients developed in the embryos
      of Haao-null or Kynu-null mice owing to NAD deficiency."
    explanation: Establishes NAD deficiency, rather than another consequence of
      the gene lesion, as the proximate cause of the malformations.
  - reference: PMID:41630685
    reference_title: "Timing of NAD Deficiency During Organogenesis Dictates Defect Type and Penetrance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Variability in the timing of maternal metabolic perturbation
      corresponded to variability in organ and tissue defect types between
      litters."
    explanation: Supports the claim that defect type follows the timing of the
      NAD deficit.
- name: Impaired Somitogenesis
  description: >-
    Vertebrae and ribs form from somites budding sequentially off the presomitic
    mesoderm during weeks 4 to 6 of human gestation. NAD deficiency during this
    window perturbs segmentation, producing the hemivertebrae, vertebral fusions
    and rib anomalies characteristic of the disorder. The lesion is in the
    metabolic substrate the forming somites depend on rather than in the
    segmentation clock itself.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: somitogenesis
    modifier: ABNORMAL
    term:
      id: GO:0001756
      label: somitogenesis
  downstream:
  - target: Vertebral segmentation defects
    causal_link_type: DIRECT
  - target: Rib anomalies
    causal_link_type: DIRECT
  - target: Hemivertebrae
    causal_link_type: DIRECT
  - target: Vertebral fusion
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34681008
    reference_title: "Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In human embryogenesis, the vertebral column develops at 4–6 weeks
      of gestation from the paraxial mesoderm (PSM) and is closely related to
      the spinal cord and other organs originating from mesoderm"
    explanation: Background from the paper's introduction rather than a study
      finding. Establishes the developmental window and tissue of origin in
      which the NAD deficit acts on the axial skeleton.
- name: Disrupted Cardiac Morphogenesis
  description: >-
    NAD deficiency during cardiac looping and septation produces structural
    heart disease. Lesions are not confined to one side of the heart, and range
    from mild aortic arch abnormalities to hypoplastic left heart.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: heart development
    modifier: ABNORMAL
    term:
      id: GO:0007507
      label: heart development
  downstream:
  - target: Congenital heart defect
    causal_link_type: DIRECT
  - target: Hypoplastic left heart syndrome
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart defects can include left-sided heart lesions,
      right-sided heart lesions, or both."
    explanation: Documents the non-lateralized distribution of cardiac lesions.
- name: Disrupted Nephrogenesis
  description: >-
    NAD deficiency during ureteric bud outgrowth and metanephric induction
    produces renal maldevelopment spanning hypoplasia and dysplasia through to
    complete bilateral agenesis, which is lethal.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: kidney development
    modifier: ABNORMAL
    term:
      id: GO:0001822
      label: kidney development
  downstream:
  - target: Renal agenesis
    causal_link_type: DIRECT
  - target: Renal hypoplasia or dysplasia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31883644
    reference_title: "Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects range from the isolated absence of both kidneys to
      multiple malformations of the vertebrae, heart, limbs, and kidney"
    explanation: Documents the renal severity range, including isolated
      bilateral renal agenesis as a presentation.
- name: Disrupted Limb Morphogenesis
  description: >-
    NAD deficiency during limb bud outgrowth and patterning produces limb
    reduction defects and disproportionate limb shortening that persists as
    short-limb short stature in survivors.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: limb development
    modifier: ABNORMAL
    term:
      id: GO:0060173
      label: limb development
  downstream:
  - target: Limb anomalies
    causal_link_type: DIRECT
  - target: Short stature with disproportionately short limbs
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost all surviving individuals have short stature, many with
      disproportionately shortened limbs."
    explanation: Documents the limb phenotype in survivors.
- name: Embryonic Growth Restriction
  description: >-
    Below a threshold of NAD availability the conceptus does not survive.
    Miscarriage is common in affected families and is part of the phenotypic
    spectrum rather than an unrelated obstetric event, so it belongs in the
    recurrence-risk conversation.
  biological_scale: ORGANISM
  downstream:
  - target: Pregnancy loss
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40689776
    reference_title: "Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Congenital NAD deficiency disorder (CNDD) is an example of such
      recurrent malformations with variable expressivity, and miscarriages are
      also frequent among affected families"
    explanation: Places pregnancy loss within the disorder's spectrum.
phenotypes:
- category: Skeletal
  name: Vertebral segmentation defects
  frequency: FREQUENT
  description: >-
    Hemivertebrae and vertebral fusion are the characteristic axial lesions, and
    are usually multiple. Scoliosis follows from the segmentation defect rather
    than arising independently.
  phenotype_term:
    preferred_term: Vertebral segmentation defect
    term:
      id: HP:0003422
      label: Vertebral segmentation defect
  sequelae:
  - target: Scoliosis
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertebral anomalies, including hemivertebrae and vertebral fusion,
      occur frequently, often with rib anomalies."
    explanation: GeneReviews documents the specific vertebral lesions and their
      frequency.
- category: Skeletal
  name: Hemivertebrae
  description: >-
    Failure of formation of one half of a vertebral body, typically at multiple
    non-contiguous levels.
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertebral anomalies, including hemivertebrae and vertebral fusion,
      occur frequently"
    explanation: Names hemivertebrae as a documented lesion.
- category: Skeletal
  name: Vertebral fusion
  description: Failure of segmentation producing block vertebrae.
  phenotype_term:
    preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including hemivertebrae and vertebral fusion, occur frequently"
    explanation: Names vertebral fusion as a documented lesion.
- category: Skeletal
  name: Rib anomalies
  description: >-
    Rib malformation accompanies the vertebral segmentation defect, as ribs and
    vertebrae derive from the same somites.
  phenotype_term:
    preferred_term: Abnormal rib morphology
    term:
      id: HP:0000772
      label: Abnormal rib morphology
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occur frequently, often with rib anomalies"
    explanation: Documents co-occurring rib involvement.
- category: Skeletal
  name: Scoliosis
  description: >-
    Progressive spinal curvature secondary to asymmetric vertebral segmentation;
    monitored to skeletal maturity.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "At each visit until skeletal maturity: monitoring for scoliosis."
    explanation: Scoliosis is monitored to skeletal maturity, which implies it is
      expected. The quote states the surveillance, not the phenotype.
- category: Cardiovascular
  name: Congenital heart defect
  frequency: FREQUENT
  description: >-
    Structural heart disease is one of the four cardinal organ systems affected.
    Both left-sided and right-sided lesions occur, sometimes together.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital NAD deficiency disorder (CNDD) is a multisystem
      condition in which cardiac, renal, vertebral, and limb anomalies are
      common, mimicking the clinical features described in VACTERL association."
    explanation: Establishes cardiac involvement as one of the defining organ
      systems.
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with heart defects, for example, ranging from relatively mild
      abnormalities of the aortic arch to life-threatening hypoplastic left
      heart"
    explanation: Documents the severity range within the cardiac phenotype,
      which is why this entry binds the general term rather than a specific
      lesion.
- category: Cardiovascular
  name: Hypoplastic left heart syndrome
  subtype: VCRL3
  description: >-
    The most severe end of the cardiac spectrum, reported in individuals with
    NADSYN1-associated disease. Its occurrence is the argument for sequencing
    the CNDD genes in a child presenting with congenital anomalies rather than
    treating the cardiac lesion as isolated.
  phenotype_term:
    preferred_term: hypoplastic left heart syndrome
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:35491967
    reference_title: Further description of two patients with biallelic variants
      in NADSYN1 in association with cardiac and vertebral anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one patient had hypoplastic left heart syndrome (HLHS) and one had
      an aortic coarctation and transverse hypoplasia of the aortic arch,
      suggesting that NADSYN1 sequencing should be performed in children
      presenting with congenital anomalies"
    explanation: Reports hypoplastic left heart in an individual with biallelic
      NADSYN1 variants.
- category: Renal
  name: Renal agenesis
  notes: >-
    Not evenly distributed across subtypes. In the largest genotyped NADSYN1
    series the kidneys were the least frequently affected of the four cardinal
    systems (3 of 12), and the reported adult with NADSYN1-associated disease
    had no renal or urinary tract malformation at all, so a normal renal
    ultrasound does not argue against the diagnosis.
  description: >-
    Unilateral or bilateral absence of the kidneys. Bilateral agenesis can be
    the sole malformation and is lethal.
  phenotype_term:
    preferred_term: Renal agenesis
    term:
      id: HP:0000104
      label: Renal agenesis
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal anomalies may be severe, including dysplasia/hypoplasia and
      renal agenesis."
    explanation: Names renal agenesis among the documented renal lesions.
- category: Renal
  name: Renal hypoplasia or dysplasia
  description: Reduced renal mass or disorganized renal parenchyma.
  phenotype_term:
    preferred_term: Renal dysplasia
    term:
      id: HP:0000110
      label: Renal dysplasia
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal anomalies may be severe, including dysplasia/hypoplasia"
    explanation: Names dysplasia and hypoplasia as documented renal lesions.
- category: Skeletal
  name: Short stature with disproportionately short limbs
  frequency: VERY_FREQUENT
  description: >-
    Almost all survivors are short, and the shortening is often disproportionate
    with limbs affected more than trunk.
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost all surviving individuals have short stature, many with
      disproportionately shortened limbs."
    explanation: Gives both the manifestation and its near-universal frequency
      among survivors.
- category: Neurological
  name: Developmental delay or intellectual disability
  frequency: FREQUENT
  description: >-
    Reported in more than half of affected individuals, though some have normal
    development. The reported frequency is likely biased by early mortality,
    since some individuals died of their malformations before development could
    be assessed.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay / intellectual disability has been reported in
      more than half of affected individuals, although some affected individuals
      have had normal development, and some individuals succumbed to their
      congenital anomalies before developmental assessment could be performed."
    explanation: States the frequency and the ascertainment caveat behind it.
- category: Craniofacial
  name: Cleft palate
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less common features may include cleft palate, eye
      anomalies, sensorineural hearing loss, tracheoesophageal fistula,
      polysplenia, anteriorly displaced anus, tethered spinal cord, cystic
      hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."
    explanation: GeneReviews lists cleft palate among the less common features.
- category: Ophthalmological
  name: Eye anomalies
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less common features may include cleft palate, eye
      anomalies, sensorineural hearing loss"
    explanation: Lists eye anomalies among the less common features.
- category: Ophthalmological
  name: Ptosis
  frequency: OCCASIONAL
  description: >-
    Ptosis and strabismus are named among the anomalies for which standard
    treatment is recommended, and bilateral ptosis was present in the reported
    adult with NADSYN1-associated disease.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Supportive care includes standard treatment for congenital
      anomalies (congenital heart defects, cleft palate, limb anomalies,
      scoliosis, tethered spinal cord, renal anomalies, tracheoesophageal
      fistula / pyloric stenosis / laryngeal web, polysplenia, and
      strabismus/ptosis)"
    explanation: GeneReviews lists ptosis among the anomalies requiring standard
      treatment, which implies it occurs in this disorder rather than stating
      the phenotype directly.
  - reference: PMID:36649848
    reference_title: "Adult patient diagnosed with NADSYN1 associated congenital
      NAD deficiency and analysis of NAD levels to be published in: European
      Journal of Medical Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unequal leg length as well as bilateral ptosis, cleft palate and
      asymmetric dysmorphic facial features"
    explanation: Reports bilateral ptosis in a genetically confirmed affected
      individual.
- category: Auditory
  name: Sensorineural hearing loss
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eye anomalies, sensorineural hearing loss, tracheoesophageal
      fistula"
    explanation: Lists sensorineural hearing loss among the less common
      features.
- category: Gastrointestinal
  name: Tracheoesophageal fistula
  frequency: OCCASIONAL
  description: >-
    Part of the VACTERL-like overlap. Its presence is one of the features that
    makes CNDD hard to separate clinically from VACTERL association.
  phenotype_term:
    preferred_term: Tracheoesophageal fistula
    term:
      id: HP:0002575
      label: Tracheoesophageal fistula
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensorineural hearing loss, tracheoesophageal fistula,
      polysplenia"
    explanation: Lists tracheoesophageal fistula among the less common features.
- category: Gastrointestinal
  name: Anteriorly displaced anus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Anteriorly placed anus
    term:
      id: HP:0001545
      label: Anteriorly placed anus
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "polysplenia, anteriorly displaced anus, tethered spinal cord"
    explanation: Lists anteriorly displaced anus among the less common features.
- category: Immunological
  name: Polysplenia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Polysplenia
    term:
      id: HP:0001748
      label: Polysplenia
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tracheoesophageal fistula, polysplenia, anteriorly displaced anus"
    explanation: Lists polysplenia among the less common features.
- category: Neurological
  name: Tethered spinal cord
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tethered cord
    term:
      id: HP:0002144
      label: Tethered cord
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anteriorly displaced anus, tethered spinal cord, cystic hygroma"
    explanation: Lists tethered spinal cord among the less common features.
- category: Lymphatic
  name: Cystic hygroma
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cystic hygroma
    term:
      id: HP:0000476
      label: Cystic hygroma
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tethered spinal cord, cystic hygroma, epilepsy"
    explanation: Lists cystic hygroma among the less common features.
- category: Neurological
  name: Epilepsy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less common features may include cleft palate, eye
      anomalies, sensorineural hearing loss, tracheoesophageal fistula,
      polysplenia, anteriorly displaced anus, tethered spinal cord, cystic
      hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."
    explanation: Lists epilepsy among the less common features.
- category: Endocrine
  name: Hypothyroidism
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less common features may include cleft palate, eye
      anomalies, sensorineural hearing loss, tracheoesophageal fistula,
      polysplenia, anteriorly displaced anus, tethered spinal cord, cystic
      hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."
    explanation: Lists hypothyroidism among the less common features.
- category: Endocrine
  name: Hypoparathyroidism
  frequency: OCCASIONAL
  description: >-
    Requires ongoing serum calcium monitoring in affected individuals.
  phenotype_term:
    preferred_term: Hypoparathyroidism
    term:
      id: HP:0000829
      label: Hypoparathyroidism
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other less common features may include cleft palate, eye
      anomalies, sensorineural hearing loss, tracheoesophageal fistula,
      polysplenia, anteriorly displaced anus, tethered spinal cord, cystic
      hygroma, epilepsy, hypothyroidism, and hypoparathyroidism."
    explanation: Lists hypoparathyroidism among the less common features.
- category: Reproductive
  name: Pregnancy loss
  description: >-
    Miscarriage is frequent in affected families and represents the severe end
    of the NAD deficiency spectrum, where the conceptus does not survive.
  phenotype_term:
    preferred_term: Miscarriage and embryo loss
  notes: >-
    Left unbound. HPO codes this concept under Pregnancy history
    (HP:0200067, Recurrent spontaneous abortion) and Prenatal death
    (HP:0034241), neither of which is reachable from the Phenotypic abnormality
    root that the PhenotypeTerm enum expands from, so no valid binding exists.
    Recorded as free text rather than forced onto a term that means something
    else.
  evidence:
  - reference: PMID:32015132
    reference_title: "NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Biallelic loss-of-function variants in HAAO or KYNU, two genes of
      the nicotinamide adenine dinucleotide (NAD) synthesis pathway, are
      causative of congenital malformation and miscarriage in humans and mice."
    explanation: States that the same lesions cause miscarriage as well as
      malformation. The sentence names humans, but it is the framing of a mouse
      study, so it is graded for the publication it comes from.
  - reference: PMID:41170824
    reference_title: Identification of potential NAD-related biomarkers of
      recurrent miscarriage risk.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Women with a history of recurrent miscarriage have higher blood,
      plasma, and urine concentrations of NAD Salvage Pathway excretion
      products, and urinary excretion of nicotinamide (NAM) is also elevated,
      compared to control women."
    explanation: Human evidence linking NAD metabolism to recurrent miscarriage.
      It is a study of women with recurrent miscarriage generally, not a CNDD
      cohort, so it supports the connection without establishing it in this
      disorder.
- category: Skeletal
  name: Limb anomalies
  frequency: FREQUENT
  description: >-
    Structural limb malformation is the "L" of VCRL and one of the four cardinal
    organ systems. In the largest genotyped series the limbs were the third most
    frequently affected system, ahead of the kidneys.
  phenotype_term:
    preferred_term: Abnormal limb bone morphology
    term:
      id: HP:0002813
      label: Abnormal limb bone morphology
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital abnormalities mostly affected the vertebrae (10 of 12),
      heart (9 of 12), and limbs (8 of 12) while less frequently affecting the
      kidneys (3 of 12)."
    explanation: Quantifies limb involvement in a genotyped CNDD series and
      places it above renal involvement in that cohort.
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, renal, vertebral, and limb anomalies are common"
    explanation: GeneReviews names limb anomalies among the common features.
- category: Dermatological
  name: Pellagra-like dermatitis
  subtype: VCRL3
  description: >-
    A postnatal, life-threatening manifestation reported in two siblings with
    complete loss-of-function NADSYN1 variants. Unlike the malformations, which
    are fixed in utero, this is an ongoing consequence of continuing NAD
    deficiency and was prevented by nicotinamide supplementation. It is the one
    place in the cited literature where supplementation produced a clinical
    rather than a biochemical benefit in a patient.
  phenotype_term:
    preferred_term: pellagra-like dermatitis
    term:
      id: HP:0011123
      label: Inflammatory abnormality of the skin
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both siblings, however, experienced previously unseen
      life-threatening episodes of pellagra-like dermatitis, a characteristic
      postnatal consequence of NAD deficiency (15) that has not been reported
      previously in NADSYN1 deficiency."
    explanation: First report of this manifestation in NADSYN1 deficiency.
- category: Craniofacial
  name: Facial dysmorphism
  frequency: FREQUENT
  description: >-
    Mild facial dysmorphism was present in the majority of a genotyped series and
    is proposed as a feature that helps separate CNDD from VACTERL association at
    the bedside.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild facial dysmorphism (7 of 12) and craniofacial (6 of 12),
      growth (5 of 12), neurodevelopmental (4 of 12), and central nervous system
      (3 of 12) abnormalities"
    explanation: Gives the observed frequency of facial dysmorphism in a
      genotyped CNDD series.
- category: Neurological
  name: Microcephaly
  description: >-
    Reported in an affected individual and persisting despite nicotinamide
    supplementation that otherwise improved development, which is one reason the
    postnatal benefit of supplementation is not treated as settled here.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "F7.II.3 had shown developmental progress to a level consistent with
      age, but remained microcephalic with mild improvement in growth
      parameters"
    explanation: Documents microcephaly in a genotyped individual, and that it
      did not resolve on supplementation.
- category: Ophthalmological
  name: Strabismus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "tracheoesophageal fistula / pyloric stenosis / laryngeal web,
      polysplenia, and strabismus/ptosis"
    explanation: GeneReviews lists strabismus among the anomalies requiring
      standard treatment, which implies it occurs in this disorder.
- category: Gastrointestinal
  name: Pyloric stenosis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pyloric stenosis
    term:
      id: HP:0002021
      label: Pyloric stenosis
  evidence:
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "tracheoesophageal fistula / pyloric stenosis / laryngeal web"
    explanation: GeneReviews lists pyloric stenosis among the anomalies
      requiring standard treatment, which implies it occurs in this disorder.
- category: Respiratory
  name: Laryngeal web
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Laryngeal web
    term:
      id: HP:0005950
      label: Laryngeal web
  evidence:
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "pyloric stenosis / laryngeal web, polysplenia"
    explanation: GeneReviews lists laryngeal web among the anomalies requiring
      standard treatment, which implies it occurs in this disorder.
biochemical:
- name: Decreased circulating NAD
  notes: >-
    Reduced plasma NAD is the direct biochemical consequence of the enzymatic
    block and is the finding that should trigger sequencing of the three CNDD
    genes when a suggestive malformation pattern is present.
  biomarker_term:
    preferred_term: Decreased circulating nicotinamide adenine dinucleotide
      concentration
    term:
      id: HP:6000405
      label: Decreased circulating nicotinamide adenine dinucleotide
        concentration
  presence: PRESENT
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients had reduced levels of circulating NAD."
    explanation: Directly documents the biochemical abnormality in affected
      individuals.
  - reference: PMID:36951206
    reference_title: "Clinical heterogeneity of NADSYN1-associated VCRL syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased plasmatic levels of NAD should then strongly encourage
      the screening for any of the genes responsible for a NAD deficiency
      disorder."
    explanation: Supports the diagnostic role of the measurement.
- name: Elevated circulating 3-hydroxyanthranilic acid
  subtype: VCRL1
  context: >-
    The substrate immediately upstream of HAAO, predicted to accumulate when
    3-hydroxyanthranilate 3,4-dioxygenase activity is lost.
  biomarker_term:
    preferred_term: Elevated circulating 3-hydroxyanthranilic acid concentration
    term:
      id: HP:6000703
      label: Elevated circulating 3-hydroxyanthranilic acid concentration
  notes: >-
    PREDICTED, NOT OBSERVED. No cited source reports a measured elevation of
    3-hydroxyanthranilic acid in a HAAO-deficient individual. The founding study
    quantified kynurenine-pathway metabolites in patient plasma but names
    neither this analyte nor a direction, so `presence` is deliberately left
    unset and this record stands as a testable prediction from the position of
    the enzymatic block. Contrast the sibling KYNU marker below, where the
    urinary elevation was actually measured.
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We tested the function of the variant by using assays of in vitro
      enzyme activity and by quantifying metabolites in patient plasma."
    directness: INDIRECT
    explanation: Establishes only that plasma kynurenine-pathway metabolites
      were measured in these patients. It names neither this analyte nor a
      direction, which is why this record is marked predicted, not observed.
- name: Elevated urinary xanthurenic acid
  subtype: VCRL2
  notes: >-
    3-hydroxykynurenine accumulating behind the kynureninase block is
    transaminated to xanthurenic acid and excreted, giving a urinary marker that
    confirmed the diagnosis in a KYNU-deficient patient.
  biomarker_term:
    preferred_term: Elevated urinary xanthurenic acid level
    term:
      id: HP:6000121
      label: Elevated urinary xanthurenic acid level
  presence: PRESENT
  evidence:
  - reference: PMID:34200361
    reference_title: "A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased xanthurenic acid excretion in the urine confirmed the
      genetic diagnosis."
    explanation: Reports the urinary finding and its diagnostic use in KYNU
      deficiency.
environmental:
- name: Maternal dietary NAD precursor insufficiency during pregnancy
  description: >-
    Low maternal intake of tryptophan and vitamin B3 lowers the NAD precursor
    supply reaching the conceptus. In mice this alone causes the malformation
    spectrum in genetically normal embryos, and combined with a single
    heterozygous pathway allele it produces a markedly worse outcome than either
    factor separately.
  presence: PRESENT
  effect: Lowers embryonic NAD, causing malformations and embryo loss
  influences_mechanisms:
  - target: Insufficient Maternal NAD Precursor Provision
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Dietary restriction of both NAD precursors is the exposure that establishes
      inadequate maternal provision.
    evidence:
    - reference: PMID:32015132
      reference_title: "NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "When the dietary undersupply was combined with a maternal
        heterozygous variant in Haao, which alone does not cause NAD deficiency
        or malformations, the incidence of embryo loss and malformations was
        significantly higher, suggesting a gene-environment interaction."
      explanation: Establishes the exposure acting on maternal NAD provision and
        its interaction with genotype.
  evidence:
  - reference: PMID:32015132
    reference_title: "NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our data show that NAD deficiency as a cause of embryo loss and
      congenital malformation is not restricted to the rare cases of biallelic
      mutations in NAD synthesis pathway genes."
    explanation: Supports treating maternal dietary insufficiency as an
      independent environmental cause.
  - reference: PMID:34748060
    reference_title: "Effect of maternal dietary niacin intake on congenital
      anomalies: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The meta-analysis showed that expectant mothers with an
      insufficient niacin intake were significantly more likely to have babies
      with congenital abnormalities (odds ratio 1.13, 95% confidence interval
      1.02-1.24) compared to mothers with adequate niacin intake."
    explanation: The human counterpart to the mouse dietary experiments. It is a
      population-level association across all congenital anomalies, not a CNDD
      cohort, so it supports the exposure being consequential in humans without
      establishing this mechanism in any individual pregnancy.
  review_notes: >-
    ECTO was searched for a term denoting dietary insufficiency or deficiency of
    an NAD precursor; ECTO models exposures to substances, not their absence, and
    the only niacin terms found (ECTO:0900032, ECTO:9002151) denote exposure to
    niacin, which is the opposite claim. Left unbound rather than bound to an
    inverted term.
- name: Gestational niacin supplementation
  description: >-
    Vitamin B3 supplementation during pregnancy raises maternal and embryonic
    NAD and prevents the malformations in mouse models. The choice of vitamer
    matters and depends on where the block sits: nicotinic acid entering through
    the Preiss-Handler pathway still requires NADSYN1, so NADSYN1-null mothers
    need amidated precursors that bypass the terminal step.
  presence: PRESENT
  effect: Protective; restores embryonic NAD and prevents malformation
  exposure_term:
    preferred_term: exposure to niacin (b3) via ingestion
    term:
      id: ECTO:0900032
      label: exposure to niacin (b3) via ingestion
  influences_mechanisms:
  - target: Embryonic NAD Deficiency
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: DIRECT
    description: >-
      Supplementation restores the precursor supply and prevents the NAD deficit
      that drives the malformations.
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In null mice, the prevention of NAD deficiency during gestation
        averted defects."
      explanation: Demonstrates that correcting the NAD deficit prevents the
        downstream malformations.
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Niacin supplementation during gestation prevented the
      malformations in mice."
    explanation: Establishes the protective effect of the exposure.
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise
      NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required
      supplementation with amidated NAD precursors (nicotinamide or nicotinamide
      mononucleotide) bypassing their metabolic block."
    explanation: Supports the claim that vitamer choice depends on the position
      of the enzymatic block.
treatments:
- name: Antenatal NAD precursor supplementation
  description: >-
    Vitamin B3 supplementation before and during a subsequent at-risk pregnancy
    is the only intervention that addresses the mechanism rather than its
    consequences, and it is preventive rather than curative: it must be in place
    during organogenesis, which is largely complete before most affected
    pregnancies are recognized. The prevention evidence is from mouse models; no
    human trial has shown prevention of CNDD in an at-risk pregnancy, so this is
    a mechanistically motivated recommendation, not a proven one. The choice of
    vitamer is likewise a mouse result: in Nadsyn1-null mice nicotinic acid was
    not sufficient and amidated precursors were required, and that has not been
    tested in humans.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: nutritional supplementation with an NAD precursor
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: nicotinic acid
      term:
        id: CHEBI:15940
        label: nicotinic acid
    - preferred_term: nicotinamide
      term:
        id: CHEBI:17154
        label: nicotinamide
    - preferred_term: nicotinamide mononucleotide
      term:
        id: CHEBI:50383
        label: nicotinamide mononucleotide
  target_mechanisms:
  - target: Embryonic NAD Deficiency
    treatment_effect: RESTORES
    description: >-
      Raises the maternal precursor pool so that embryonic NAD stays above the
      organogenesis threshold.
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In null mice, the prevention of NAD deficiency during gestation
        averted defects."
      explanation: Shows the intervention acts by correcting this specific
        mechanism node.
  evidence:
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We reproduced NADSYN1-dependent CNDD in mice and assessed various
      maternal NAD precursor supplementation strategies to prevent adverse
      pregnancy outcomes."
    explanation: Describes the supplementation strategy this treatment records.
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional clinical trials are needed before accurate dosage
      recommendations required to prevent CNDD-dependent malformation can be
      made."
    explanation: Establishes that the human dosing question is open, which is
      why this treatment is described as mechanistically motivated rather than
      established.
- name: Postnatal amidated NAD precursor supplementation
  description: >-
    Distinct from the antenatal preventive use: metabolome data suggest affected
    individuals continue to have inadequate NAD after birth, so maintaining NAD
    with amidated precursors may be warranted beyond the prenatal window. The
    concrete indication is postnatal NAD-dependent disease rather than the fixed
    malformations, which supplementation cannot undo: nicotinamide prevented
    recurrent life-threatening pellagra-like dermatitis in two NADSYN1-null
    siblings, and raised blood NAD in genotyped individuals. Beyond that it is a
    suggestion from the metabolome study, not established practice; GeneReviews
    records no cure and describes management as supportive.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: nutritional supplementation with an amidated NAD precursor
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: nicotinamide
      term:
        id: CHEBI:17154
        label: nicotinamide
  evidence:
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggest an ongoing need to maintain NAD levels via amidated NAD
      precursor supplementation after birth"
    explanation: States the postnatal supplementation rationale, and its
      hedged framing is why this entry does not present it as established.
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "A 1-month-old individual with CNDD caused by biallelic
      loss-of-function HAAO variants was reported to have improved in length and
      development after 3 months of NA supplementation"
    explanation: A single reported human response to postnatal supplementation.
      Note the precursor here is nicotinic acid, not an amidated one, and the
      subtype is HAAO, where the Preiss-Handler route is intact; it therefore
      supports postnatal supplementation in general rather than the amidated
      requirement this treatment is named for.
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "F7.II.3 at 100 mg/d for 6 weeks, who exhibited a 115% increase in
      blood NAD levels in comparison with unsupplemented conditions"
    explanation: >-
      The amidated-precursor human data proper, showing nicotinamide raised
      blood NAD in a genotyped individual.
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "F9.II.4 at 200 mg/d for 8 weeks to prevent life-threatening
      NADSYN1-dependent pellagra-like dermatitis (NDPD; Supplemental Results).
      To our knowledge, this is the first report of NDPD and its prevention"
    explanation: The strongest human indication for postnatal supplementation in
      the cited literature, and the only clinical rather than biochemical
      benefit reported.
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monitoring of progress in more supplemented individuals with CNDD,
      and for longer time frames, is necessary before it becomes clear whether
      these developmental phenotypes are indeed modifiable."
    explanation: The authors' own statement that the postnatal benefit is not
      yet established, which is why this treatment is not presented as standard
      of care.
  - reference: PMID:36649848
    reference_title: "Adult patient diagnosed with NADSYN1 associated congenital
      NAD deficiency and analysis of NAD levels to be published in: European
      Journal of Medical Genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The NAD pool rose approximately 25% after supplementation with
      nicotinamide, a NAD precursor for the salvage pathway."
    explanation: The one human measurement showing postnatal nicotinamide
      raises the NAD pool in an affected individual. It is a biochemical
      response in a single patient, not a clinical outcome.
- name: Supportive management of congenital anomalies
  description: >-
    There is no cure. Management is standard treatment of each malformation and
    of the functional consequences, coordinated across cardiology, nephrology,
    orthopaedics, ENT, ophthalmology and developmental services, with structured
    surveillance for scoliosis, hearing, vision, thyroid function, calcium and
    renal function. Medications that impair kidney function should be avoided in
    those with a solitary kidney or known renal impairment.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  - preferred_term: Renal dysplasia
    term:
      id: HP:0000110
      label: Renal dysplasia
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  - preferred_term: Tethered cord
    term:
      id: HP:0002144
      label: Tethered cord
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no cure for CNDD."
    explanation: Establishes that management is supportive rather than curative.
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Avoidance of medications that
      impair kidney function, in those with renal aplasia (solitary kidney)
      and/or known impaired kidney function."
    explanation: Records the GeneReviews drug-safety warning reflected in this
      treatment's description.
- name: Genetic counselling and family evaluation
  description: >-
    Autosomal recessive recurrence risk is 25% per pregnancy. Because
    malformations can be occult, at-risk relatives should be evaluated once the
    familial variants are known. Uniparental isodisomy has been documented as a
    route to biallelic KYNU loss, which changes the recurrence risk for that
    family and is a reason to establish the mechanism rather than assume
    biparental inheritance.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is appropriate to clarify the genetic status of apparently
      asymptomatic older and younger at-risk relatives of an affected individual
      in order to identify as early as possible those who would benefit from
      more in-depth evaluation for occult congenital malformations."
    explanation: Records the recommendation to evaluate at-risk relatives.
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance
      of being affected, a 50% chance of being an asymptomatic carrier, and a
      25% chance of being unaffected and not a carrier."
    explanation: The recurrence risk figures this entry cites elsewhere.
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "carrier testing for at-risk relatives and prenatal and
      preimplantation genetic testing are possible."
    explanation: Records the reproductive testing options available once the
      familial variants are known.
animal_models:
- name: Haao-null mouse
  species: Mouse
  genotype: Haao-/-
  category: Genetic
  publication: PMID:28792876
  description: >-
    CRISPR-Cas9 engineered null mouse that develops the human malformation
    spectrum when maternal NAD precursor supply is limited, and is protected by
    gestational niacin.
  genes:
  - preferred_term: HAAO
    term:
      id: hgnc:4796
      label: HAAO
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin
      Supplementation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We engineered mouse models with similar variants using the CRISPR
      (clustered regularly interspaced short palindromic repeats)-Cas9 system."
    explanation: Describes how this model was constructed, establishing that it
      carries the orthologous lesion rather than an unrelated null allele.
  modeled_mechanisms:
  - target: Embryonic NAD Deficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces both the NAD deficit and the resulting multi-organ malformation
      pattern seen in patients with the orthologous lesion.
    limitations: >-
      Penetrance depends on the maternal diet used, so a result from this model
      is conditional on the dietary regimen and cannot be read as an unqualified
      genotype-phenotype statement.
    readouts:
    - name: Embryonic NAD level
      target: Embryonic NAD Deficiency
      direction: DECREASED
      interpretation: Direct measurement of the deficit this node describes.
      evidence:
      - reference: PMID:40689776
        reference_title: "Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "mouse embryos with genetic disruption of NAD de novo synthesis
          (Haao-/-) were more susceptible to CNDD when maternal circulatory
          nicotinamide was limited, as their yolk sacs cannot generate NAD de
          novo from tryptophan"
        explanation: Reports the embryonic NAD vulnerability measured in this
          genotype.
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defects similar to those in the patients developed in the
        embryos of Haao-null or Kynu-null mice owing to NAD deficiency."
      explanation: Supports treating this model as informative for the NAD
        deficiency node.
  - target: Embryonic NAD Deficiency
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      Gestational niacin supplementation in the null mother prevents the
      malformations, which is the rescue arm establishing that the NAD deficit
      is the operative lesion.
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Niacin supplementation during gestation prevented the
        malformations in mice."
      explanation: Documents the rescue.
- name: Kynu-null mouse
  species: Mouse
  genotype: Kynu-/-
  category: Genetic
  publication: PMID:28792876
  description: >-
    Null mouse for the kynureninase step, developing the same malformation
    spectrum as the Haao-null model.
  genes:
  - preferred_term: KYNU
    term:
      id: hgnc:6469
      label: KYNU
  evidence:
  - reference: PMID:28792876
    reference_title: "NAD Deficiency, Congenital Malformations, and Niacin
      Supplementation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Defects similar to those in the patients developed in the embryos
      of Haao-null or Kynu-null mice owing to NAD deficiency."
    explanation: Reports the malformation phenotype in this genotype.
  modeled_mechanisms:
  - target: Embryonic NAD Deficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Confirms that the phenotype follows the pathway block rather than a
      gene-specific moonlighting function, since two different enzymatic steps
      give the same result.
    limitations: >-
      As with the Haao model, expression of the phenotype is conditional on the
      maternal dietary NAD precursor regimen.
    evidence:
    - reference: PMID:28792876
      reference_title: "NAD Deficiency, Congenital Malformations, and Niacin Supplementation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defects similar to those in the patients developed in the
        embryos of Haao-null or Kynu-null mice owing to NAD deficiency."
      explanation: Supports this model as informative for the NAD deficiency
        node.
- name: Nadsyn1-null mouse
  species: Mouse
  genotype: Nadsyn1-/-
  category: Genetic
  publication: PMID:38357931
  description: >-
    Model of the terminal-step block, used to work out which B3 vitamer can
    rescue a given genotype.
  genes:
  - preferred_term: NADSYN1
    term:
      id: hgnc:29832
      label: NADSYN1
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We reproduced NADSYN1-dependent CNDD in mice and assessed various
      maternal NAD precursor supplementation strategies to prevent adverse
      pregnancy outcomes."
    explanation: Establishes that this model reproduces the disorder, which is
      the basis for treating it as informative here.
  modeled_mechanisms:
  - target: De Novo NAD Synthesis Pathway Enzymatic Block
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces NADSYN1-dependent CNDD and shows that the position of the block
      determines which precursors can bypass it.
    limitations: >-
      The vitamer-specificity result is a mouse finding; the corresponding human
      supplementation strategy has not been tested in a trial.
    evidence:
    - reference: PMID:38357931
      reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We reproduced NADSYN1-dependent CNDD in mice and assessed
        various maternal NAD precursor supplementation strategies to prevent
        adverse pregnancy outcomes."
      explanation: Supports this model as informative for the enzymatic block
        node.
- name: Slc6a19 heterozygous mouse
  species: Mouse
  genotype: Slc6a19+/-
  category: Genetic
  publication: PMID:36374036
  description: >-
    Not a pathway-enzyme model. Heterozygous loss of the neutral amino acid
    transporter limits maternal tryptophan availability, showing that a gene
    outside NAD synthesis can produce the same disorder.
  evidence:
  - reference: PMID:36374036
    reference_title: Maternal heterozygosity of Slc6a19 causes metabolic
      perturbation and congenital NAD deficiency disorder in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pregnant Slc6a19+/- mice were fed diets depleted of vitamin B3, so
      that tryptophan was the source of NAD during gestation."
    explanation: Describes the model and the dietary condition it requires,
      which is the basis for treating it as informative here.
  modeled_mechanisms:
  - target: Insufficient Maternal NAD Precursor Provision
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Models the maternal-supply arm rather than the embryonic enzymatic block,
      producing CNDD malformations through restricted tryptophan transport.
    limitations: >-
      Requires a vitamin B3-depleted maternal diet to manifest, and no human
      SLC6A19 carrier has been reported with this outcome, so the human
      relevance is inferred rather than demonstrated.
    evidence:
    - reference: PMID:36374036
      reference_title: "Maternal heterozygosity of Slc6a19 causes metabolic perturbation and congenital NAD deficiency disorder in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our results show that genes not directly involved in NAD
        synthesis can affect NAD metabolism and cause CNDD."
      explanation: Supports this model as informative for the maternal provision
        node.
- name: ATDA-treated zebrafish
  species: Zebrafish
  genotype: Wild type treated with 2-amino-1,3,4-thiadiazole
  category: Chemical
  publication: PMID:39829932
  description: >-
    A chemically induced rather than genetic model, valuable because zebrafish
    embryos develop externally and can be watched in real time. Nicotinamide
    rescues the defects dose-dependently, which is the same rescue logic as the
    mouse models in a second vertebrate.
  evidence:
  - reference: PMID:39829932
    reference_title: A zebrafish model of nicotinamide adenine dinucleotide
      (NAD(+)) deficiency-derived congenital disorders.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we describe a zebrafish model of NAD+ disruption to begin to
      model CNDD and VACTERL association phenotypes, assessing developmental
      anomalies in real-time."
    explanation: Establishes the model and what it is for.
  modeled_mechanisms:
  - target: Embryonic NAD Deficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces cardiac and craniofacial anomalies and their nicotinamide
      rescue, but through a teratogen rather than a lesion in a CNDD gene.
    limitations: >-
      ATDA is a chemical inhibitor of NAD metabolism, not a model of biallelic
      HAAO/KYNU/NADSYN1 loss, so off-target effects cannot be excluded. The
      defect set is also zebrafish-specific: neural tube and tail defects rather
      than the vertebral, renal and limb malformations that define the human
      disorder.
    evidence:
    - reference: PMID:39829932
      reference_title: A zebrafish model of nicotinamide adenine dinucleotide
        (NAD(+)) deficiency-derived congenital disorders.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Treatment of zebrafish embryos with 2-amino-1,3,4-thiadiazole
        (ATDA), a teratogen known to disrupt NAD+ metabolism, resulted in neural
        tube, craniofacial, cardiac, and tail defects. These defects were
        rescued by the administration of nicotinamide (NAM) in a dose-dependent
        manner."
      explanation: Reports both the phenotype and its NAD-precursor rescue,
        which is what makes this model informative for the NAD deficiency node.
diagnosis:
- name: Molecular genetic testing of HAAO, KYNU and NADSYN1
  description: >-
    The diagnostic criterion. Exome, genome or a targeted panel covering the
    three pathway genes establishes the diagnosis in a proband with suggestive
    findings. Copy-number analysis matters as well as sequencing, since a
    homozygous exon deletion and a uniparental isodisomy have each produced
    biallelic loss in reported cases.
  evidence:
  - reference: PMID:37499065
    reference_title: Congenital NAD Deficiency Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of CNDD is established in a proband with suggestive
      findings and biallelic pathogenic variants in HAAO, KYNU, or NADSYN1
      identified by molecular genetic testing."
    explanation: States the diagnostic criterion.
  - reference: PMID:34200361
    reference_title: A Homozygous Deletion of Exon 5 of KYNU Resulting from a
      Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL
      Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using Trio-Exome analysis and CGH array analysis in combination
      with long range PCR, we have identified a novel homozygous copy number
      variant (CNV) encompassing exon 5 of KYNU"
    explanation: Shows that sequencing alone can miss the causal lesion, which is
      why copy-number analysis belongs in the workup.
- name: Circulating NAD metabolome signature
  description: >-
    Plasma NAD and kynurenine-pathway metabolite profiling identifies affected
    individuals and, because the accumulating species depends on which enzyme is
    lost, points to the gene to sequence. GeneReviews establishes the diagnosis
    on biallelic pathogenic variants in HAAO, KYNU or NADSYN1; the metabolome is
    the finding that prompts that testing.
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of CNDD is established in a proband with suggestive
      findings and biallelic pathogenic variants in HAAO, KYNU, or NADSYN1
      identified by molecular genetic testing."
    explanation: States the diagnostic criterion.
  - reference: PMID:38357931
    reference_title: "A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data collectively improve clinical diagnostics of
      NADSYN1-dependent CNDD"
    explanation: Supports the metabolome's diagnostic contribution.
differential_diagnoses:
- name: VACTERL association
  description: >-
    CNDD is clinically indistinguishable from VACTERL association in many
    individuals, and the overlap is the main reason the disorder is
    underdiagnosed. The practical separator is that CNDD has a testable
    biochemical and molecular basis, so a VACTERL-like presentation is a reason
    to measure NAD rather than to stop at a descriptive label.
  evidence:
  - reference: PMID:37499065
    reference_title: "Congenital NAD Deficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac, renal, vertebral, and limb anomalies are common,
      mimicking the clinical features described in VACTERL association"
    explanation: States the phenotypic overlap that drives the differential.
- name: Catel-Manzke syndrome
  description: >-
    A KYNU-deficient individual has been reported with features overlapping both
    VCRL and Catel-Manzke syndrome, so the two can present together.
  evidence:
  - reference: PMID:34200361
    reference_title: "A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in an individual presenting with overlapping features of VCRL and
      Catel-Manzke Syndrome"
    explanation: Documents the reported overlap.
- name: Hydroxykynureninuria without malformation
  description: >-
    KYNU variants that leave residual kynureninase activity produce the
    biochemical picture of this disorder, hydroxykynureninuria with xanthurenic
    aciduria, in individuals who have no congenital malformations. It is the same
    gene and the same metabolic block, separated only by how much enzyme is left,
    which is why a raised xanthurenic acid alone does not establish CNDD. The
    cited review does not report the zygosity of the reported brothers' variant,
    so this entry does not assert it; the mechanistic claim it does make is about
    residual enzyme activity, not about allele configuration.
  evidence:
  - reference: PMID:34200361
    reference_title: A Homozygous Deletion of Exon 5 of KYNU Resulting from a
      Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL
      Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Christensen et al. described two brothers with a missense variant
      in KYNU, resulting in a threonine to alanine amoinoacid exchange
      (p.Thr198Ala), presenting with hydroxykynureninuria and xanthurenic
      aciduria but without congenital malformations"
    explanation: Documents the allelic condition and that it lacks the
      malformations that define CNDD.
  - reference: PMID:34200361
    reference_title: A Homozygous Deletion of Exon 5 of KYNU Resulting from a
      Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL
      Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A residual activity of kynureninase in these patients with
      consequently higher levels of plasma NAD+ could explain the distinct
      phenotype"
    explanation: Gives the proposed basis for the split, residual activity
      keeping NAD above the threshold organogenesis needs.
- name: Congenital vertebral malformation of other genetic cause
  description: >-
    In a cohort ascertained for congenital vertebral malformation, rare NADSYN1
    variants were recovered in a minority of patients, though as heterozygous
    variants of uncertain significance rather than the biallelic loss that
    defines CNDD. Most congenital vertebral malformation is not CNDD, and the
    segmentation-clock disorders remain the larger differential.
  evidence:
  - reference: PMID:34681008
    reference_title: "Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings demonstrated that functional variants in NADSYN1 were
      involved in the complex genetic etiology of CVMs"
    explanation: Places CNDD as one contributor among several to congenital
      vertebral malformation.
discussions:
- discussion_id: human_efficacy_of_antenatal_b3_prevention
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does periconceptional and gestational vitamin B3 supplementation prevent
    congenital NAD deficiency disorder in an at-risk human pregnancy?
  rationale: >-
    Prevention in mice is well established and the mechanism is clear, but no
    trial or observational cohort has tested whether supplementation in a
    subsequent pregnancy after an affected child prevents recurrence. The only
    human data are population-level: a meta-analysis of 14 case-control studies
    associates insufficient maternal niacin intake with congenital anomalies in
    general (PMID:34748060), which is a different and much weaker claim. The gap matters because the intervention is cheap
    and low-risk while the outcome it would prevent is often lethal, and because
    families are being counselled now on mouse data alone. It is also unusually
    hard to close, since the disorder is rare enough that a conventional
    randomized trial is unlikely to be feasible.
  attaches_to:
  - treatments#Antenatal NAD precursor supplementation
  - pathophysiology#Embryonic NAD Deficiency
  evidence:
  - reference: PMID:38357931
    reference_title: A metabolic signature for NADSYN1-dependent congenital NAD
      deficiency disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional clinical trials are needed before accurate dosage
      recommendations required to prevent CNDD-dependent malformation can be
      made."
    explanation: The authors state the human evidence is absent, which is the
      gap this discussion records.
- discussion_id: mouse_diet_conditionality_vs_human_ascertainment
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does the mouse dependence of the CNDD phenotype on maternal dietary NAD
    precursor restriction hold in humans, whose background vitamin B3 intake is
    generally higher and often fortified?
  rationale: >-
    In every mouse model the malformation phenotype is conditional on a
    B3-restricted maternal diet; null animals on a replete diet are largely
    protected. Human CNDD patients, by contrast, are ascertained without any
    documented maternal dietary deficiency. Either human de novo synthesis
    contributes a larger share of embryonic NAD than the mouse experiments
    imply, or unmeasured variation in maternal precursor status is doing work
    that nobody has quantified. Which of these is true determines whether
    maternal nutritional assessment belongs in the counselling of an at-risk
    family, so this is not merely a modelling curiosity.
  attaches_to:
  - pathophysiology#Insufficient Maternal NAD Precursor Provision
  - animal_models#Haao-null mouse
  evidence:
  - reference: PMID:32015132
    reference_title: NAD deficiency due to environmental factors or
      gene-environment interactions causes congenital malformations and
      miscarriage in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "C57BL/6J wild-type mice had offspring exhibiting similar
      malformations when their supply of the NAD precursors tryptophan and
      vitamin B3 in the diet was restricted during pregnancy."
    explanation: Documents the dietary conditionality of the mouse phenotype
      that this mismatch is about.
- discussion_id: unestablished_downstream_effectors_of_embryonic_nad_loss
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which NAD-dependent processes actually fail in the embryo when NAD falls,
    and why do they fail in these organs and not others?
  rationale: >-
    Every node in this entry below Embryonic NAD Deficiency is an organ-level
    description. The layer that would connect them, the NAD-dependent effectors
    in a proliferating embryonic progenitor (PARP-mediated ADP-ribosylation,
    sirtuin signalling, redox and ATP supply), is not curated here because it has
    not been established. It also has to explain a selectivity problem: NAD is
    required in every cell, yet the malformations fall on a specific and
    reproducible set of organs. Until this is resolved, the pathograph explains
    that NAD deficiency causes the malformations, not how, and any downstream
    node here should be read as a description rather than a mechanism.
  attaches_to:
  - pathophysiology#Embryonic NAD Deficiency
  - phenotypes#Developmental delay or intellectual disability
  evidence:
  - reference: PMID:39829932
    reference_title: A zebrafish model of nicotinamide adenine dinucleotide
      (NAD(+)) deficiency-derived congenital disorders.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, the mechanism by which NAD+ deficiency causes CNDD
      developmental anomalies has not been determined, nor has NAD+ deficiency
      been definitively linked to VACTERL association."
    explanation: States directly that the mechanism connecting the NAD deficit
      to the anomalies is unknown, which is the gap this discussion records.
- discussion_id: nad_deficiency_as_pleiotropic_malformation_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is NAD deficiency a shared mechanism behind other recurrent malformation
    constellations currently classified as separate entities?
  rationale: >-
    It has been proposed that NAD deficiency is a pleiotropic mechanism uniting
    VACTERL, limb-body wall complex, OEIS complex, MURCS, sirenomelia and
    others. The proposal is explicitly a hypothesis, and its author states that
    no confirmatory experimental studies in humans exist. Recording it as an
    open question rather than as background is the honest treatment: if it were
    true, the scope of this entry would be considerably larger than three genes.
  attaches_to:
  - disease#Congenital Vertebral-Cardiac-Renal Anomalies Syndrome
  evidence:
  - reference: PMID:35484986
    reference_title: "NAD+ deficiency in human congenital malformations and
      miscarriage: A new model of pleiotropy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "it is important to emphasize there have been no confirmatory
      experimental studies in humans to prove this hypothesis."
    explanation: The proposing author states the hypothesis is unconfirmed,
      which is why it is recorded as an open question rather than as content.
notes: >-
  Entry shape follows the decision recorded on issue #8549, which closed the
  standalone VCRL1 curation request in favour of a single root entry spanning
  the congenital NAD deficiency pathway with VCRL1 (HAAO), VCRL2 (KYNU) and
  VCRL3 (NADSYN1) as subtypes. GeneReviews independently treats the three genes
  as one disorder, "congenital NAD deficiency disorder", which supports that
  shape.

  No conforms_to declaration is made against the
  axial_segmentation_serial_homology module. That module is built around the
  Notch segmentation clock (DLL3, MESP2, LFNG, HES7, TBX6), and there is no
  evidence that NAD deficiency acts through that oscillator; the vertebral
  phenotypes converge without the mechanisms doing so. The relationship is
  recorded here rather than asserted as conformance.
review_notes: >-
  just discover-datasets returned a single GEO candidate (geo:GSE243441, bulk
  RNA-seq in bladder cancer) matched on the gene symbol NADSYN1 alone. It is a
  gene-only match with no relation to this disorder, and was rejected rather
  than curated. No datasets block is therefore present.

📚

References & Deep Research

References

1

PMID:37499065

Congenital NAD Deficiency Disorder

No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Self-review fixes: claim-evidence mismatches, missing limb and postnatal phenotypes · 2026-09-03T08:06:37Z · View source

Adversarial self-review of the entry created in the preceding session record, run in a fresh context against the dismech-pr-review skill. It returned REQUEST_CHANGES with six blocking findings; all six were verified against the cached source text before acting, and all six were real. Fixes below. Claim-evidence mismatches (blocking). PMID:34681008 was cited on genetic[NADSYN1] as CAUSATIVE evidence. The paper reports "eight rare NADSYN1 heterozygous nonsynonymous variants" classified "as VUS" in a congenital vertebral malformation cohort. Monoallelic variants of uncertain significance do not evidence a causative biallelic gene-disease relationship, and the item contradicted the entry's own quoted framing that every CNDD case arises from biallelic loss of function. The item was removed from genetic; its correct use in differential_diagnoses is unchanged. biochemical[Elevated circulating 3-hydroxyanthranilic acid] asserted presence: PRESENT on a snippet that says only that metabolites were measured, naming neither the analyte nor a direction. No cached source reports the elevation in a HAAO-deficient patient. presence removed, notes rewritten to state the record is a prediction from the position of the enzymatic block, and the evidence item marked directness: INDIRECT. treatments[Postnatal amidated NAD precursor supplementation] rested on a case of "NA supplementation" in a HAAO patient. In that paper NA is nicotinic acid, which is not an amidated precursor, in the subtype where the Preiss-Handler route is intact, so the evidence did not support the claim it was attached to. Re-explained as evidence for postnatal supplementation in general, and the paper's actual amidated-precursor human data added: a 115% rise in blood NAD on nicotinamide, and prevention of life-threatening NADSYN1-dependent pellagra-like dermatitis. Omissions (blocking). No limb phenotype existed, despite limb anomalies being the L of VCRL, named in the GeneReviews sentence already quoted twice in the entry, and affecting 8 of 12 in the largest genotyped series - ahead of the kidneys. The Disrupted Limb Morphogenesis node was asserting a phenotype the entry never recorded. Added, with the 8-of-12 snippet, and wired as a downstream target. Pellagra-like dermatitis was absent. It is the only postnatal manifestation in the cited literature that supplementation has been shown to prevent, and the strongest human indication for postnatal treatment. Added as a VCRL3 phenotype. PMID:34748060, a meta-analysis of 14 case-control studies (35,743 women) associating insufficient maternal niacin intake with congenital anomalies, was fetched into this PR's cache and cited nowhere. That left the environmental exposure entry, marked PRESENT on a human disease, supported only by MODEL_ORGANISM evidence, which CLAUDE.md forbids. Worse, the antenatal-prevention discussion asserted "the human evidence is entirely absent" while that paper sat uncited in the same PR. Now cited on the exposure with directness: INDIRECT, and the discussion narrowed to say no trial has tested supplementation in an at-risk pregnancy and the only human data are population-level. Human/mouse boundary. Three places stated murine results as general fact and were hedged: the VCRL3 vitamer-specificity claim (a Nadsyn1-null mouse result, untested in humans, and stated flatly in both the subtype description and the antenatal treatment), and the timing-determines-defect claim on Embryonic NAD Deficiency. Other corrections. The quinolinate-biosynthesis DECREASED descriptor was removed: it is false for VCRL3, where the NADSYN1 block sits downstream of quinolinate, so a node-scoped tag was wrong for a third of the disorder; the reason is recorded in the node's notes and two chemical entities replace it. "Two steps upstream of NAD" was wrong (there are several). Two unsourced comparative claims (a spondylocostal-dysostosis contrast, a neural-crest cardiopathy contrast) were cut rather than left as authoritative-sounding assertions with nothing behind them. The Haao-null RESCUES link pointed at maternal provision rather than at the NAD deficit it corrects. The VCRL3 "unaffected adults" claim was re-cited to the paper that actually says "complete absence of malformation". Four evidence_source grades were fixed, including a MODEL_ORGANISM grade that was the sole support for a human phenotype. Two en-dash-to-hyphen snippet drifts were normalised so the quotes are literal substrings, not merely dash-normalised matches. Additions. A KNOWLEDGE_GAP discussion recording that the effector layer between NAD loss and organ failure is unestablished, and that this leaves the pathograph explaining that NAD deficiency causes the malformations but not how, nor why these organs. A zebrafish ATDA model (PMID:39829932) as a second species with a nicotinamide rescue. Molecular genetic testing split out as its own diagnosis entry from the metabolome adjunct, with the copy-number caveat that a KYNU exon deletion and a UPD2 both produced biallelic loss. Facial dysmorphism, microcephaly, strabismus, pyloric stenosis and laryngeal web phenotypes. GeneReviews recurrence-risk figures and reproductive testing options quoted rather than paraphrased. Not done. No disease-level prevalence record: the GeneReviews cohort count (27 individuals from 25 families) appears in the deep-research reading of the full chapter but not in the cached abstract, and no other cached source gives a disease-level figure, so it is left as a gap rather than asserted from an unquotable source. The prevalence record remains VCRL3-scoped and says so. Validation after fixes: `just validate` 115/115 snippets verified; `just validate-disorders` passes. check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence all pass. Compliance 94.9% global (95.2% weighted) over a larger denominator than before.

Create: Congenital Vertebral-Cardiac-Renal Anomalies Syndrome (CNDD; VCRL1/2/3) · 2026-09-03T07:45:50Z · View source

Requested as "curate vertebral, cardiac, renal, and limb defects syndrome 1" (VCRL1, MONDO:0060554). Curated as a parent-level entry instead of a standalone VCRL1 file, following the decision recorded when issue #8549 was closed: LUMP_INTO_PARENT, with VCRL1 (HAAO), VCRL2 (KYNU) and VCRL3 (NADSYN1) as has_subtypes under MONDO:0020831. GeneReviews independently treats the three genes as one disorder, "congenital NAD deficiency disorder" (PMID:37499065), which supports that shape. The VCRL1 stub (stubs/Vertebral_Cardiac_Renal_And_Limb_Defects_Syndrome_1.yaml) is deleted by this change; no stubs existed for VCRL2 or VCRL3. Deep research. falcon was requested (the /curate default) and failed authentication with a 403 on both attempts, so the run was re-issued with dr_fallback='--fallback' rather than substituting a provider by hand. That run fell back to openscientist and its report records fell_back: true, requested_provider: falcon and both provider attempts in frontmatter. A claude_code run was executed in parallel while openscientist was queued. Both reports were used and both are committed. research/...-deep-research-openscientist.md: 9/9 references resolved, 0 unresolved, 9/9 on topic; 27/28 terms resolved with one obsolete (GO:0043420, not used here) and three benign label variants. Its causal chain independently matches the one curated here. Its claim of a "homozygous HAAO exon-5 deletion" is a report error - PMID:34200361 describes a KYNU exon-5 deletion - and was not propagated. research/...-deep-research-claude_code.md: 16 web searches, 22 turns, 24 citations. Its reference-validation section was added retroactively with `just validate-research-reference`: 15/15 references resolved, 0 unresolved, 0 off topic. Term validation of that report (`just validate-research-terms`) flagged real problems, and none of its suggested CURIEs were copied across unchecked. The report proposed HP:0004392 for hypoplastic left heart; HP:0004392 is "Prune belly". It labelled GO:0034354 as "NAD biosynthesis via nicotinamide riboside salvage pathway" when that term is the de novo route from tryptophan, and UBERON:0002298 as "vertebral column" when it is brainstem. It also offered two obsolete terms (HP:0001180, GO:0043420). Every binding in the entry was resolved independently with OAK and validated by `just validate-terms`. GeneReviews baseline (Step 3b). PMID:37499065 "Congenital NAD Deficiency Disorder" was found, fetched, tagged GeneReviews in the top-level references block, and used as the phenotype baseline. Every phenotype named in its Clinical Characteristics section is captured: congenital heart defects, short stature with disproportionately shortened limbs, vertebral anomalies (hemivertebrae, vertebral fusion) with rib anomalies, renal dysplasia/hypoplasia/agenesis, developmental delay/intellectual disability, and each of the less common features (cleft palate, eye anomalies, sensorineural hearing loss, tracheoesophageal fistula, polysplenia, anteriorly displaced anus, tethered spinal cord, cystic hygroma, epilepsy, hypothyroidism, hypoparathyroidism). Its Agents/Circumstances to Avoid item (avoid nephrotoxic medications with a solitary or impaired kidney) is recorded in the supportive-care treatment description with the GeneReviews quote as evidence. Mechanism. Built as a causal chain rather than a list: enzymatic block -> embryonic NAD deficiency -> per-organ morphogenesis nodes -> the corresponding phenotypes, with maternal NAD precursor provision entering as a second, independent input to the same convergence node. That shape is the substantive claim of the literature (PMID:32015132 shows the malformations arise in genetically normal embryos on a restricted maternal diet), and it is what lets the environmental and treatment blocks attach to a single node instead of duplicating the pathology. Human/mouse boundary. All prevention evidence is murine. The antenatal supplementation treatment is described as mechanistically motivated rather than established and carries the authors' own statement that clinical trials are still needed (PMID:38357931); a KNOWLEDGE_GAP discussion records the absent human evidence, and a HUMAN_MODEL_MISMATCH discussion records that every mouse phenotype is conditional on a B3-restricted maternal diet while human patients are ascertained without documented maternal deficiency. Deliberate omissions. No conforms_to against axial_segmentation_serial_homology: that module is built on the Notch segmentation clock, and there is no evidence NAD deficiency acts through that oscillator, so the relationship is recorded in notes rather than asserted as conformance (this follows the guidance left on issue #8549). No datasets block: `just discover-datasets` returned one GEO candidate (geo:GSE243441), a bladder-cancer RNA-seq study matched on the NADSYN1 gene symbol alone, which is a gene-only false positive and was rejected; the reason is recorded in the entry's review_notes. The "Pregnancy loss" phenotype is left unbound because HPO codes the concept under Pregnancy history and Prenatal death, neither reachable from the Phenotypic abnormality root the PhenotypeTerm enum expands from; the reason is in that phenotype's notes. The maternal dietary insufficiency exposure is likewise unbound: ECTO models exposure to substances, not their absence, and its niacin terms assert the opposite claim. Citations used but not from the report: the GeneReviews chapter, the NADSYN1 cohort papers (PMID:34681008, PMID:36951206), the KYNU/UPD2 case (PMID:34200361), the gene-environment mouse work (PMID:32015132, PMID:36374036) and the timing/yolk-sac studies (PMID:40689776, PMID:41630685) were found by direct PubMed search. PMID:36649848 (the 30-year-old NADSYN1 patient: renal sparing, and a ~25% NAD pool rise on nicotinamide) came from the openscientist report and is the only human measurement of a response to supplementation in the entry. Preference was given to PMIDs over DOIs throughout, so every evidence item is snippet-checked by the gating validator. Validation. `just validate` passes with 97/97 snippets verified against the reference cache. The batched pre-PR gate `just validate-disorders kb/disorders/Congenital_Vertebral-Cardiac-Renal_Anomalies_Syndrome.yaml` passes schema, term and reference validation. Also run and passing: check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence. `just compliance` reports 95.5% global (weighted 95.8%).

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-sonnet-5 24 citations 2026-09-03T07:33:33.611644

1. Disease Information

Overview. Congenital Vertebral-Cardiac-Renal Anomalies Syndrome is the Orphanet/MONDO name for a rare, genetically heterogeneous, autosomal recessive multiple-congenital-anomaly disorder caused by biallelic loss-of-function variants in the de novo NAD⁺ (nicotinamide adenine dinucleotide) biosynthesis pathway. The umbrella clinical/molecular entity is now widely referred to in the literature as Congenital NAD Deficiency Disorder (CNDD) — a name adopted after the causal mechanism was discovered in 2017. CNDD is genetically heterogeneous, comprising three OMIM-numbered subtypes distinguished by which pathway enzyme is disrupted:

Subtype	OMIM	Gene	Enzyme
VCRL1	#617660	HAAO	3-hydroxyanthranilate 3,4-dioxygenase
VCRL2	#617661	KYNU	Kynureninase
VCRL3	#618845	NADSYN1	Glutamine-dependent NAD⁺ synthetase

Notably, the specific Orphanet/MONDO entity named "Congenital vertebral-cardiac-renal anomalies syndrome" (ORPHA:521438; also indexed as MONDO_0020831 on Open Targets) is described with the severe, infancy-lethal phenotype (hypoplastic/absent left ventricle, transposition of the great arteries, absent pulmonary trunk, hypoplastic/absent kidneys) that corresponds most closely to VCRL3/NADSYN1 (OMIM #618845), while the broader GeneReviews chapter "Congenital NAD Deficiency Disorder" (NBK593504) treats all three genes (HAAO/KYNU/NADSYN1) as one clinically overlapping spectrum. Curators should be aware of this granularity mismatch: the named "vertebral-cardiac-renal anomalies syndrome" label leans toward the NADSYN1-associated, most-severe end of the CNDD spectrum, but shares identical mechanism, evidence base, and management guidance with the HAAO- and KYNU-associated forms.

Key identifiers: - OMIM: #617660 (VCRL1/HAAO), #617661 (VCRL2/KYNU), #618845 (VCRL3/NADSYN1) - Orphanet: ORPHA:521438 - MONDO: MONDO:0020831 (per Open Targets); the term is also cataloged as MONDO:0030077 in some secondary listings — verify against the live MONDO release before binding - GARD (NCATS/NIH): Disease ID 17961 - GeneReviews: NBK593504 ("Congenital NAD Deficiency Disorder") - MedGen Concept IDs: C4540004 (VCRL1), C4540014 (VCRL2), C5394250 (VCRL3) - Gene OMIM (*): HAAO 604521; KYNU 605197; NADSYN1 608285

Synonyms: VCRL syndrome; Vertebral, Cardiac, Renal, and Limb Defects syndrome (1/2/3); Congenital NAD Deficiency Disorder (CNDD); HAAO-related / KYNU-related / NADSYN1-related multiple congenital anomaly syndrome; historically overlaps in the literature with "VACTERL-like association of genetic cause."

Source of information: Nearly all clinical knowledge derives from aggregated disease-level resources — case series and cohort reviews assembled from published case reports (OMIM, GeneReviews, Orphanet) rather than large prospective EHR cohorts, reflecting the rarity of the condition (GeneReviews July 2023 update: 27 reported individuals from 25 families worldwide, of whom 16 were living at time of publication).

2. Etiology

Disease causal factors — genetic. CNDD is caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in one of three non-redundant genes encoding sequential enzymes of the de novo NAD⁺ synthesis pathway from dietary tryptophan: HAAO, KYNU, and NADSYN1. The founding paper, Shi et al. 2017 (PMID: 28792876, N Engl J Med 377:544–552), identified "variants … in two genes encoding enzymes of the kynurenine pathway, HAAO … and KYNU … Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162, HAAO p.W186, or KYNU p.V57Efs21)," and reported that "the patients had reduced levels of circulating NAD." NADSYN1 was subsequently established as a third causal gene by Szot et al. 2020 (PMID: 31883644, Am J Hum Genet 106:129–136), describing five individuals from four families with biallelic NADSYN1* variants and phenotypes "rang[ing] from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney," with "no affected individual surviv[ing] for more than three months postnatally" in that severe cohort.

Risk factors: - Genetic: Biallelic pathogenic/likely pathogenic variants in HAAO, KYNU, or NADSYN1 (per ACMG/AMP criteria, Richards et al. 2015, PMID: 25741868) are causal, not merely a risk factor — the disorder is fully penetrant when both alleles are null. Parental consanguinity substantially raises a priori risk in any autosomal recessive disorder; multiple reported families are consanguineous. A maternal chromosome 2 isodisomy (uniparental disomy) unmasking a homozygous KYNU exon-5 deletion has been documented as a distinct mechanism producing biallelic loss-of-function from a single carrier parent (Schüle et al. 2021, PMID: 34200361, Genes 12:879, "A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy … Causes Catel-Manzke-Syndrome/VCRL Syndrome"). - Environmental / maternal metabolic: Because the terminal metabolite is the same essential cofactor (NAD⁺) required in the mother's own developing embryo, maternal dietary niacin/tryptophan insufficiency, and possibly maternal illness or drugs (e.g., isoniazid, which depletes vitamin B6 needed for kynurenine-pathway flux) that impair the mother's own NAD⁺ supply during the periconceptional/early-embryonic window, are hypothesized modifiers of severity and penetrance in genetically at-risk pregnancies, based on the mouse model data below (Shi et al. 2017).

Protective factors: - Genetic: No protective alleles are established; heterozygous carriers of HAAO/KYNU/NADSYN1 variants are asymptomatic. - Environmental — niacin/nicotinamide supplementation. This is the single most important modifiable factor identified for this disease class. Shi et al. 2017 showed in Haao-null and Kynu-null mouse embryos that malformations mirroring the human phenotype occur "owing to NAD deficiency," and that "niacin supplementation during gestation prevented the malformations in mice." Follow-on commentary (e.g., coverage of the Dunwoodie group's work, Victor Chang Cardiac Research Institute) proposed maternal supplementation strategies (in the range of ~140 mg/day investigated preclinically — roughly 10× the standard RDA for women) as a plausible clinical prevention strategy, though this has not yet been validated in a human interventional trial for genetically confirmed carrier couples. A broader systematic review/meta-analysis of maternal dietary niacin intake and congenital anomalies (PMID: 34748060) supports a population-level association between niacin status and malformation risk.

Gene-environment interactions. The core G×E model of this disease is that haploinsufficient/heterozygous carrier status combines with maternal NAD⁺-precursor insufficiency (low dietary tryptophan/niacin, malabsorption, or drugs interfering with kynurenine-pathway flux) to push total embryonic NAD⁺ below a mechanistic threshold during the vulnerable early-organogenesis window — while frank biallelic loss-of-function in the embryo itself produces a much larger, largely non-nutrition-rescuable NAD⁺ deficit. Mark 2022 (PMID: 35484986, Am J Med Genet A 188:2834–2849, "NAD+ deficiency in human congenital malformations and miscarriage: a new model of pleiotropy") proposes that this G×E axis underlies a wider group of overlapping malformation syndromes (VACTERL association, limb-body wall complex, pentalogy of Cantrell, OEIS complex, oculoauriculovertebral spectrum, MURCS, sirenomelia, urorectal septum malformation sequence) and recurrent miscarriage, framing NAD⁺ deficiency as a pleiotropic developmental mechanism rather than a single-syndrome cause.

3. Phenotypes

Phenotype frequencies below are drawn from the GeneReviews CNDD cohort synthesis (25–27 reported affected individuals; NBK593504, 2023 update) and the founding case series.

Category	Frequency	Detail	Suggested HP term
Congenital heart defect	100% (25/25)	Hypoplastic left heart (most common, 8 cases), tetralogy of Fallot (3), coarctation of the aorta, aortic stenosis, bicuspid aortic valve, mitral valve defects, absent pulmonary trunk, double-outlet right ventricle, ASD, PDA, transposition of the great arteries (in the most severe/NADSYN1-associated cases)	HP:0001627 (Abnormal heart morphology); HP:0004392 (Hypoplastic left heart); HP:0001636 (Tetralogy of Fallot); HP:0001680 (Coarctation of aorta)
Short stature / growth failure	92% (12/13)	Height z-scores +0.25 to −6.1; often disproportionate, with shortened limbs	HP:0004322 (Short stature)
Microcephaly	29% (7/24)	Z-scores −2.3 to −6.4	HP:0000252 (Microcephaly)
Vertebral segmentation anomalies	69% overall musculoskeletal; 18/26 vertebral specifically	Hemivertebrae, vertebral fusion, "butterfly" vertebrae, rib anomalies	HP:0003468 (Segmental instability of spine)/HP:0008619 (vertebral segmentation defect); HP:0002937 (Hemivertebrae)
Limb anomalies	29% (7/24)	Hyperphalangism, short phalanges/metacarpals with accessory ossicles, shortened metatarsals, rhizomelia/brachymelia	HP:0001180 (Hyperphalangism); HP:0009601 (Ulnar deviation)/HP:0001156 (Brachydactyly)
Cutaneous syndactyly	15% (4/26)		HP:0001762 (Talipes equinovarus) / HP:0001548
Neuromuscular anomalies	22% (6/27)	Talipes, arthrogryposis, pterygia	HP:0001371 (Flexion contracture); HP:0002829 (Arthrogryposis multiplex congenita)
Renal anomalies	59%	Dysplasia/hypoplasia (8), unilateral agenesis (6), bilateral agenesis, ureteral agenesis, hydronephrosis	HP:0000107 (Renal cyst); HP:0000089 (Renal hypoplasia/dysplasia); HP:0000122 (Unilateral renal agenesis)
Developmental delay / intellectual disability	62% (8/13)	Ranges from normal to severe; one case with global delay + autism	HP:0001263 (Global developmental delay); HP:0001249 (Intellectual disability)
Sensorineural hearing loss	15% (4/27)	With inner ear abnormalities	HP:0000407 (Sensorineural hearing impairment)
Craniofacial dysmorphism	46%	Brachycephaly, prominent supraorbital ridges, hyper/hypotelorism, up/downslanting palpebral fissures, depressed nasal bridge, micrognathia, cleft soft palate — "no recognizable facial gestalt"	HP:0000369 (Low-set ears); HP:0000508 (Ptosis); HP:0000175 (Cleft palate)
Endocrine	rare	Congenital hypothyroidism (2 cases), hypoparathyroidism (1 case)	HP:0000821 (Hypothyroidism); HP:0000829 (Hypoparathyroidism)
GI/other visceral	occasional	Tracheoesophageal fistula, polysplenia, hepatomegaly, anteriorly displaced anus, pyloric stenosis	HP:0002575 (Tracheoesophageal fistula); HP:0009800 (Polysplenia)
Ophthalmologic	occasional	Strabismus, ptosis, ocular crystals, hypopigmented iris with nodules	HP:0000486 (Strabismus)
Seizures	rare	One reported Lennox-Gastaut-type case	HP:0002510

Onset: All features are congenital/present at birth or detected prenatally by ultrasound; severity spans a spectrum from prenatal loss/termination to survival into adulthood (oldest reported living patient: age 30, Erbs et al. 2023, PMID: 36649848). Progression: structural anomalies are static congenital malformations rather than progressive; secondary sequelae (e.g., chronic kidney disease from renal hypoplasia, scoliosis progression, hearing loss impact) can evolve postnatally and require longitudinal surveillance. Quality of life impact: driven mainly by the combination of congenital heart disease, renal insufficiency, developmental/intellectual disability, and orthopedic complications; no disease-specific QoL instrument has been published, but impact is analogous to other multi-system congenital anomaly syndromes requiring lifelong multidisciplinary care.

4. Genetic/Molecular Information

Causal genes (all three are non-redundant, sequential enzymes of the de novo NAD⁺ pathway):

Gene	Locus	OMIM (gene)	HGNC	Protein	% of solved CNDD cases	Detection rate (sequence analysis)
HAAO	2p21	604521	HGNC:4796	3-hydroxyanthranilate 3,4-dioxygenase	~18%	>99%
KYNU	2q22.2	605197	HGNC:6469	Kynureninase	~41%	>99% (sequence); rare additional yield from deletion/duplication testing)
NADSYN1	11q13.4	608285	HGNC:29832	Glutamine-dependent NAD⁺ synthetase	~41%	>99%

Variant classification and type. Reported variants span nonsense (e.g., HAAO p.D162, p.W186), frameshift (KYNU p.V57Efs21), splice-site, missense (NADSYN1 p.A573T), and structural/copy-number variants (a homozygous KYNU exon-5 deletion via maternal isodisomy). All disease-causing genotypes are biallelic loss-of-function or severely hypomorphic, consistent with a straightforward loss-of-function* mechanism (no dominant-negative or gain-of-function alleles reported). ACMG/AMP criteria (PMID: 25741868) are the standard classification framework applied in the primary literature (all reported variants pathogenic/likely pathogenic).

Population allele frequency: Individual causal variants are, as expected for an ultra-rare autosomal recessive disorder, absent or present only as very rare heterozygous alleles in gnomAD; no common founder variant has been reported across the described families (each family typically carries a private variant), though the maternal UPD2 case represents a distinct, non-Mendelian recurrence mechanism.

Somatic vs. germline: Exclusively germline — this is a developmental/Mendelian disorder, not a somatic/cancer-related condition.

Functional consequences: Uniform loss of enzymatic function, verified in several studies by in vitro expression assays showing "essentially abolished" enzyme activity for KYNU truncating alleles, and confirmed physiologically by reduced circulating NAD⁺ and accumulation of upstream pathway metabolites (3-hydroxyanthranilic acid [3HAA] elevated / NAD(H) reduced for HAAO; 3-hydroxykynurenine [3HK] elevated / NAD(H) reduced for KYNU).

Modifier genes: None formally established; phenotypic variability within and across families (even with identical genotypes) suggests unidentified genetic or environmental (maternal nutritional) modifiers, consistent with the mouse data showing rescue by maternal dietary niacin.

Epigenetic information: Not established as a primary mechanism for this disorder; NAD⁺ itself is a cofactor for epigenetic enzymes (sirtuins, PARPs), so downstream epigenetic dysregulation is mechanistically plausible but not directly documented in patient tissue to date.

Chromosomal abnormalities: Not a chromosomal/copy-number syndrome per se, though the KYNU exon-5 deletion via maternal isodisomy of chromosome 2 (Schüle et al. 2021) is a structural mechanism worth noting for differential/recurrence-risk counseling.

Genetically related (allelic) disorders (per GeneReviews): - HAAO: no other associated phenotype reported. - KYNU: biallelic variants can also cause isolated hydroxykynureninuria (xanthurenic aciduria) — a biochemical excretory phenotype without the full malformation syndrome — indicating allelic/dosage heterogeneity. - NADSYN1: preliminary evidence (Lin et al. 2021, PMID: 34681008) suggests monoallelic variants may be associated with a milder spectrum of vertebral/cardiac/renal/limb/hepatic defects and intraspinal anomalies, though this requires confirmation.

Suggested GO terms for pathway annotation: - GO:0034354 — "NAD biosynthesis via nicotinamide riboside salvage pathway" (salvage, contrast pathway) - GO:0009435 — "NAD biosynthetic process" (parent term covering the de novo route) - GO:0043420 — "anthranilate metabolic process" - GO:0019805 — "quinolinate biosynthetic process" (product of the HAAO reaction, immediate NAD⁺ precursor) - GO:0033721 — "3-hydroxyanthranilate 3,4-dioxygenase activity" (HAAO molecular function) - GO:0030429 — "kynureninase activity" (KYNU molecular function) - GO:0008795 — "NAD+ synthase activity" (NADSYN1 molecular function)

5. Environmental Information

Environmental factors: The dominant environmental modifier for this specific gene-driven disorder is maternal NAD⁺-precursor (niacin/tryptophan) nutritional status during the periconceptional and early-embryonic period, as established mechanistically in the Shi et al. 2017 mouse model. This is distinct from a classical toxin-exposure etiology — the "environmental" axis here operates through nutrient sufficiency for a genetically compromised biosynthetic pathway rather than through an exogenous toxicant.

Lifestyle factors: Maternal diet quality/adequacy of niacin (vitamin B3) and tryptophan intake is the principal modifiable lifestyle factor implicated; standard prenatal multivitamins in most jurisdictions do not include niacin at the doses studied preclinically (~140 mg/day, ~10× US RDA for women), so this is an area of active clinical translation rather than settled guideline recommendation.

Infectious agents: None implicated; this is a purely genetic/metabolic developmental disorder with no known infectious trigger.

Drug/xenobiotic interactions (plausible, not disease-specific evidence): Agents that deplete vitamin B6 (a cofactor for kynurenine-pathway enzymes upstream of HAAO/KYNU, e.g., isoniazid) or otherwise impair tryptophan/kynurenine-pathway flux are biologically plausible aggravating exposures in a genetically at-risk pregnancy, based on pathway biology, though disease-specific human data linking a named xenobiotic exposure to CNDD severity have not been published.

6. Mechanism / Pathophysiology

Causal chain (numbered, from initiating lesion to clinical manifestation):

Biallelic loss-of-function variants in HAAO, KYNU, or NADSYN1 each abolish or severely reduce the catalytic activity of a sequential enzyme in the de novo NAD⁺ biosynthesis pathway that converts dietary tryptophan → kynurenine → 3-hydroxykynurenine → 3-hydroxyanthranilic acid (HAAO substrate) → quinolinic acid → nicotinic acid adenine dinucleotide (NAAD) → NAD⁺ (NADSYN1's product) — directly demonstrated by loss of enzymatic activity in expression assays (Shi et al. 2017, PMID:28792876).
This leads to accumulation of the immediate upstream metabolite for each block (3HAA for HAAO deficiency; 3HK for KYNU deficiency) and a reduction in de novo–synthesized NAD⁺ — directly measured as reduced circulating NAD⁺/NADH in affected patients and in Haao-null/Kynu-null mouse embryos (demonstrated).
Because the salvage pathway cannot fully compensate during early embryogenesis (the bulk of adult cellular NAD⁺ is normally salvage-derived, but the embryo appears to rely disproportionately on de novo synthesis in a defined developmental window), this results in a critical, tissue-wide NAD⁺ deficit specifically during early organogenesis — inferred from the mouse rescue experiments and the stereotyped, organ-selective malformation pattern rather than directly visualized in human embryos (partly inferred).
NAD⁺ deficiency impairs core NAD⁺-dependent cellular processes required for organogenesis, including its role as an electron acceptor for ATP synthesis (oxidative phosphorylation/glycolysis), and as a substrate for NAD⁺-consuming enzymes (sirtuins, PARPs, cADPR synthases) that regulate chromatin state, DNA-damage response, and cell signaling — this leads to disrupted proliferation, differentiation, and patterning signals in the developing mesoderm-derived organ primordia (largely inferred from general NAD⁺ biology; not yet organ-specifically dissected in this disease).
Because heart, kidney, and vertebral column all arise from tightly time-linked mesodermal developmental programs active in the same early post-gastrulation window, this results in the disease's signature co-occurring triad of cardiac, renal, and vertebral malformation, with limb, craniofacial, and neurodevelopmental structures affected to a variable, generally lesser degree depending on the residual NAD⁺ level (dose-dependent severity — supported by the genotype-severity gradient across HAAO/KYNU vs. the more severe NADSYN1/VCRL3 cohort).
In the most severe cases (particularly biallelic NADSYN1 loss), this leads to profound structural cardiac defects (hypoplastic/absent left ventricle, transposition of the great arteries, absent pulmonary trunk) and bilateral renal agenesis/hypoplasia incompatible with postnatal survival — resulting in pregnancy loss or death within the first year of life (demonstrated clinically; Szot et al. 2020).
In milder allelic combinations (partial residual enzyme activity), this results in the broader, non-lethal CNDD phenotypic spectrum — short stature, isolated or combined vertebral/cardiac/renal/limb anomalies, developmental delay, and hearing loss — with survival into childhood and, in the mildest known case, adulthood (demonstrated).
Restoring embryonic NAD⁺ supply via maternal dietary niacin supplementation during gestation bypasses the enzymatic block (niacin enters NAD⁺ synthesis through the separate Preiss-Handler pathway, independent of HAAO/KYNU/NADSYN1) and prevents the malformation cascade in Haao-null and Kynu-null mouse embryos — demonstrated experimentally and the strongest direct mechanistic proof of the causal chain (Shi et al. 2017).

Molecular pathways: Kynurenine pathway / tryptophan catabolism (KEGG: hsa00380 Tryptophan metabolism); de novo NAD⁺ biosynthesis pathway (KEGG: hsa00760 Nicotinate and nicotinamide metabolism; Reactome: "Tryptophan catabolism"). No canonical developmental signaling pathway (Wnt/MAPK/mTOR) has been shown to be the direct downstream effector — the current model treats NAD⁺ depletion itself, and its downstream effects on ATP generation and NAD⁺-dependent enzymes, as the proximate lesion (Dunwoodie et al. 2023 review, "Nicotinamide Adenine Dinucleotide Deficiency and Its Impact on Mammalian Development," Antioxid Redox Signal, doi:10.1089/ars.2023.0349, is the most current mechanistic synthesis).

Cellular processes: Impaired cellular bioenergetics (ATP synthesis) and NAD⁺-dependent enzymatic signaling (sirtuin-mediated deacetylation, PARP-mediated DNA repair) in rapidly proliferating embryonic mesodermal progenitors during organogenesis are the leading hypothesized cellular mechanisms; oxidative stress has also been proposed as a downstream consequence of impaired NAD⁺/NADH redox balance.

Protein dysfunction: Straightforward loss of enzymatic function (not misfolding/aggregation) for HAAO, KYNU, and NADSYN1 — nonsense, frameshift, and splice variants predominate, consistent with a null mechanism; the one recurrent missense allele (NADSYN1 p.A573T) has been functionally shown to impair NAD⁺ synthetase activity in vitro.

Metabolic changes: Central to this disease — this is fundamentally a tryptophan/NAD⁺ pathway metabolic disorder. Biochemically diagnostic findings include elevated upstream metabolites (3HAA in HAAO deficiency; 3HK, xanthurenic acid, kynurenine in KYNU deficiency) and reduced NAD⁺/NADH; a dedicated "metabolic signature" study for NADSYN1-associated disease has been published (PMC10866660) proposing a biochemical biomarker panel for diagnosis/monitoring.

Advanced/omics technologies: A 2025 preprint/publication (Dunwoodie group, bioRxiv 10.1101/2025.01.10.632366; PMID: 39829932) establishes a zebrafish model of NAD⁺ deficiency-derived congenital disorders, extending the mouse data and explicitly raising the hypothesis that CNDD and VACTERL association "possess similar underlying causes," while noting that "the mechanism by which NAD⁺ deficiency causes CNDD developmental anomalies has not been determined" at the cellular/molecular signaling level — an open mechanistic gap appropriate to flag as a KNOWLEDGE_GAP or HUMAN_MODEL_MISMATCH discussion node in a KB entry (mouse/zebrafish recapitulate gross structural phenotype and confirm niacin rescue, but the precise cell-signaling explanation for organ selectivity remains undetermined).

Suggested GO (biological process) / CL (cell type) terms: GO:0009435 (NAD biosynthetic process), GO:0006979 (response to oxidative stress), GO:0006974 (cellular response to DNA damage stimulus, PARP-relevant); relevant cell types are broadly mesodermal cardiac progenitor cells (CL:0000499), metanephric mesenchyme/nephron progenitor cells (CL:1000384), and sclerotome-derived vertebral precursor cells — none of the primary literature has yet performed single-cell resolution of the affected embryonic compartments in this specific human disorder.

7. Anatomical Structures Affected

Organ level (primary): Heart (all major structural compartments — left ventricle, outflow tract, septa, valves), kidneys (parenchyma and collecting system), vertebral column (vertebral bodies, ribs). Secondary/associated: limbs (long bones, hands/feet), craniofacial skeleton and palate, inner ear, brain (microcephaly, hydrocephalus, cerebellar hypoplasia in a subset), thyroid and parathyroid glands, spleen (polysplenia), esophagus/trachea (TEF), eyes.

Body systems involved: Cardiovascular, renal/urinary, musculoskeletal (axial and appendicular), nervous (central and peripheral/hearing), endocrine, gastrointestinal, ophthalmologic, lymphatic (cystic hygroma).

Suggested UBERON terms: UBERON:0000948 (heart); UBERON:0002113 (kidney); UBERON:0002298 (vertebral column); UBERON:0002101 (limb); UBERON:0001456 (face); UBERON:0001690 (ear); UBERON:0000955 (brain); UBERON:0002046 (thyroid gland); UBERON:0001132 (parathyroid gland); UBERON:0002106 (spleen).

Tissue/cell level: Cardiac muscle and endocardial/outflow-tract mesenchyme; nephron epithelium and metanephric mesenchyme; sclerotome-derived vertebral chondro-osseous tissue; limb bud mesenchyme/chondrocytes. Cell Ontology suggestions: CL:0000746 (cardiac muscle cell), CL:0002518 (kidney epithelial cell), CL:0000138 (chondrocyte).

Subcellular level: Mitochondria (site of NAD⁺-dependent oxidative phosphorylation; GO:0005739) and nucleus (site of NAD⁺-dependent sirtuin/PARP chromatin and DNA-repair activity; GO:0005634) are the most mechanistically relevant compartments, given NAD⁺'s dual roles as a redox cofactor and enzymatic substrate.

Localization/laterality: Renal involvement can be unilateral (agenesis in 6 cases) or bilateral; cardiac and vertebral anomalies are generally midline/structural rather than strictly lateralized; limb involvement, when present, is typically bilateral and symmetric (consistent with a systemic metabolic rather than a focal teratogenic insult).

8. Temporal Development

Onset: Congenital — all structural anomalies originate during embryonic organogenesis (roughly weeks 3–8 post-conception for the heart, kidney, and vertebral primordia), detectable prenatally by ultrasound in many cases and at birth in others. This is a true prenatal-onset disorder; there is no pediatric/adult-onset variant.

Progression: The structural malformations themselves are static (fixed at the point of embryogenesis), but their functional consequences progress postnatally — e.g., renal hypoplasia can evolve into progressive chronic kidney disease, scoliosis from vertebral segmentation defects can worsen through skeletal growth, and developmental delay/intellectual disability trajectories unfold through childhood. Disease course is therefore best described as a stable structural lesion with a progressive secondary functional burden.

Disease stages: No formal staging system exists; clinical severity is best stratified by genotype/residual enzyme activity, ranging from prenatal lethality (most severe NADSYN1 cases) to survival into adulthood (mildest reported cases, oldest known patient age 30).

Course pattern: Non-relapsing, non-remitting — a fixed congenital anomaly burden with the natural history of any structural birth-defect syndrome (i.e., defined by the severity of the initial malformations rather than an episodic or fluctuating pathobiology).

Critical period: Explicitly established mechanistically — the mouse rescue experiments (Shi et al. 2017) demonstrate that maternal niacin supplementation during gestation (i.e., during the embryonic organogenesis window) is sufficient to prevent malformation, defining early gestation as the critical intervention window for any future preventive strategy in genetically at-risk pregnancies.

9. Inheritance and Population

Epidemiology: Extremely rare — GeneReviews (2023) documents 27 reported affected individuals from 25 families worldwide across all three genes combined, almost certainly an underascertainment given likely underdiagnosis of stillbirths/terminations and phenotypic overlap with VACTERL association. No formal population prevalence or incidence estimate (per 100,000) has been published; the disorder should be classified as ultra-rare / cases-in-literature only for prevalence-banding purposes.

Inheritance pattern: Autosomal recessive for all three subtypes (HAAO/KYNU/NADSYN1). GeneReviews: "The diagnosis of CNDD is established in a proband with suggestive findings and biallelic pathogenic variants in HAAO, KYNU, or NADSYN1."

Penetrance: Essentially complete for biallelic null genotypes, based on the consistency of the malformation phenotype across reported families, though expressivity (see below) varies widely.

Expressivity: Markedly variable, even for identical genotypes within a family, ranging from isolated bilateral renal agenesis to the full multi-organ syndrome — reflecting the hypothesized gene-environment (maternal NAD⁺ precursor sufficiency) interaction described in Section 2.

Genetic anticipation: Not applicable/not reported (mechanism is enzymatic loss-of-function, not a repeat-expansion disorder).

Germline mosaicism: Not directly documented but should be considered in recurrence-risk counseling per general AR-disorder practice; the GeneReviews chapter recommends confirmatory parental testing partly to exclude occult mosaicism/de novo scenarios.

Founder effects: No population-specific founder variant has been established; each reported family generally carries a private variant.

Consanguinity: A recognized risk factor, as for any rare autosomal recessive disorder; several reported families are consanguineous.

Carrier frequency: Not established (too rare for population carrier-frequency databases such as gnomAD to yield a meaningful estimate for any single pathogenic allele).

Population demographics: No ethnic, geographic, or sex-specific enrichment has been reported; cases have been described across multiple continents/ancestries in the literature (North America, Europe, Australia most represented, reflecting the discovering research groups' referral bases rather than a true epidemiological signal). No male:female skew is expected or reported for an autosomal recessive disorder.

Age distribution: By definition, congenital onset; postnatal survivors range from neonatal death (severe cases) to age 30 at last published report.

10. Diagnostics

Suggestive findings (GeneReviews): prenatal/postnatal imaging showing congenital heart defects (left- and/or right-sided), renal anomalies (aplasia/hypoplasia/dysplasia), vertebral anomalies (butterfly/hemi-/wedge/fused vertebrae), shortened long bones (rhizomelia/brachymelia), and short metacarpals with accessory ossicles; clinical findings of short stature, microcephaly, dysmorphic (cupped/low-set) ears, sensorineural hearing loss, nuchal redundancy/cystic hygroma, cutaneous syndactyly, hyperphalangism, developmental delay/ID, sacral dimple, clubfeet; and a compatible autosomal recessive family history (though its absence does not exclude the diagnosis).

Establishing the diagnosis: Biallelic pathogenic variants in HAAO, KYNU, or NADSYN1 confirmed by molecular genetic testing, via either: 1. A gene-targeted VACTERL-association multigene panel including HAAO, KYNU, NADSYN1 (sequence + deletion/duplication analysis), or 2. Exome or genome sequencing when the phenotype overlaps with other multiple-congenital-anomaly syndromes.

Biochemical/metabolomic testing (research/adjunct use): plasma/urine metabolite panels showing elevated upstream kynurenine-pathway intermediates (3HAA, 3HK, xanthurenic acid, kynurenine) and reduced NAD⁺/NADH; a dedicated NADSYN1 "metabolic signature" panel has been proposed (PMC10866660) as a functional confirmatory/monitoring tool alongside genetic testing.

Imaging: Fetal/postnatal echocardiography (cardiac defects), renal/bladder ultrasound (renal anomalies), spinal radiographs ± CT (vertebral segmentation), spinal ultrasound (<3 months) or MRI (>3 months) if dysraphism/tethered cord suspected, brain MRI if microcephaly/seizures/neuromuscular findings.

Differential diagnosis (GeneReviews, summarized): - VACTERL association — the closest clinical mimic; distinguished by CNDD's relative rarity of anal atresia and tracheoesophageal fistula, and its higher frequency of disproportionate short stature, developmental delay, and facial dysmorphism. Mechanistic overlap is now an active research question (see Section 6). - Townes-Brocks syndrome (SALL1, AD) — dysplastic/hearing-impaired ears and thumb malformations much more prominent; imperforate anus in ~84%. - Catel-Manzke syndrome (TGDS, AR) — distinctive hand malformation with accessory ossicles and index-finger shortening; Pierre Robin sequence more common, cardiac/vertebral/renal anomalies rarer. - Fanconi anemia (~23 genes, AR/AD/X-linked) — bone marrow failure and cancer predisposition absent in CNDD; structural anomaly rates markedly lower. - 22q11.2 deletion syndrome (AD) — immune deficiency and palatal anomalies far more prominent. - Teratogen-induced phenocopies: diabetic embryopathy, thalidomide embryopathy, and valproate embryopathy each share partial overlap but differ in the frequency/pattern of neural tube, cleft, and limb-reduction defects (van de Putte et al. 2020, PMID: 32596782, is the key comparative reference for the VACTERL differential specifically).

Screening: No population newborn-screening program exists (metabolite panel is not part of standard newborn screening); prenatal ultrasound is the practical first-line detection modality given the structural nature of the anomalies; carrier/prenatal/preimplantation genetic testing is available once a family's causal variants are identified.

11. Outcome/Prognosis

Survival/mortality: Highly genotype/severity-dependent. In the most severe cohort (biallelic NADSYN1, Szot et al. 2020), "no affected individual survived for more than three months postnatally," with outcomes spanning isolated bilateral renal agenesis to lethal multi-organ malformation. Across the full GeneReviews cohort of 27 individuals, 9 did not survive (5 pregnancy termination/loss, 4 deaths in the first year from severe structural defects), while 16 were living, including one individual reported alive at age 30 (Erbs et al. 2023) — demonstrating that survival to adulthood is possible with milder genotypes and modern multidisciplinary management.

Morbidity/function: Long-term morbidity is driven by chronic kidney disease (in survivors with significant renal hypoplasia), residual cardiac lesions requiring ongoing cardiology follow-up, orthopedic complications (scoliosis, limb-length discrepancy), sensorineural hearing loss, and variable intellectual disability/developmental delay (up to 62% in the reviewed cohort). No standardized disability or QoL instrument has yet been applied to this population in the literature.

Complications: Progressive chronic kidney disease/hypertension (renal survivors), tethered spinal cord (in those with spinal dysraphism), feeding/aspiration issues from TEF or laryngeal web, hypothyroidism/hypoparathyroidism, and — where polysplenia is present — functional asplenia/infection risk.

Recovery potential: Structural anomalies themselves are not reversible; outcome depends on surgical/medical correction of individual organ defects (cardiac surgery, orthopedic correction, hearing aids, etc.) rather than on treating the underlying metabolic lesion, since no NAD⁺-repletion treatment for affected individuals postnatally has yet been validated or recommended (see Section 12).

Prognostic factors: Genotype/gene (NADSYN1-associated disease trends more severe/lethal than HAAO- or KYNU-associated disease in the literature to date, though formal genotype-phenotype correlation is explicitly stated as unestablished by GeneReviews), severity and combination of organ involvement (cardiac + bilateral renal disease carries the worst prognosis), and gestational NAD⁺ status (maternal nutritional modifier, per the mouse model).

12. Treatment

No disease-modifying cure exists. Management is supportive and organ-specific, coordinated through a multidisciplinary genetics/cardiology/nephrology/orthopedics/developmental team, per GeneReviews (NBK593504):

Congenital heart defects: Standard pediatric cardiology/cardiac surgical management per lesion type (NCIT:C15329, Surgical Procedure; NCIT:C49236, Therapeutic Procedure).
Renal anomalies: Nephrology monitoring of function/blood pressure; avoid nephrotoxic agents in those with solitary/hypoplastic kidneys.
Vertebral/orthopedic anomalies (scoliosis, clubfoot, limb anomalies): Standard orthopedic management (NCIT:C16186, Orthopedic Surgical Procedure); neurosurgical management if tethered cord.
Cleft palate: Craniofacial team management.
Hearing loss: Hearing aids/otolaryngology referral (NCIT device pattern applies).
GI anomalies (TEF, pyloric stenosis, laryngeal web): Gastroenterology/otolaryngology surgical management.
Polysplenia: Hematology/immunology monitoring for functional asplenia.
Developmental delay/intellectual disability: Early intervention (0–3), developmental preschool, IEP/504 supports, physical/occupational/speech therapy, ABA for autism-spectrum features, developmental pediatrics.
Seizures: Standard anti-seizure medication (no CNDD-specific agent shown superior).
Endocrine (hypothyroidism, hypoparathyroidism): Standard endocrinology management/hormone replacement (NCIT:C15986, Pharmacotherapy).
Ophthalmologic findings (strabismus, ptosis): Standard ophthalmologic management.
Family/psychosocial: Genetic counseling, social work, palliative/home-nursing referral where indicated.

A notable and reportable gap: despite NAD⁺ deficiency being the established root mechanism, and despite gestational niacin supplementation preventing malformation in mouse models (Shi et al. 2017), the current GeneReviews chapter does not recommend niacin/nicotinamide/NAD⁺/NMN/NR supplementation as a treatment for affected individuals postnatally, and no human interventional trial of maternal or child NAD⁺-precursor supplementation for this specific disorder has been published as of the most recent literature reviewed. This is an important, explicit KNOWLEDGE_GAP for a KB mechanism entry: the mechanistic and preclinical rationale for prevention (pre-conception/gestational niacin supplementation in confirmed carrier couples) is strong, but translation into a validated treatment/prevention guideline for humans remains an active, unresolved research question.

Experimental/preclinical therapeutics: Gestational niacin supplementation is the sole experimentally validated intervention to date, demonstrated only in Haao-null/Kynu-null mouse embryos (Shi et al. 2017) and now being extended in the 2025 zebrafish CNDD model (PMID: 39829932) to further dissect the rescue mechanism. No registered clinical trial (ClinicalTrials.gov) specific to CNDD/VCRL syndrome niacin prophylaxis was identified in the sources reviewed.

Screening/counseling role of niacin data: Even absent a formal trial, the preclinical prevention data is directly relevant to genetic counseling for known carrier couples planning a subsequent pregnancy, and several review/commentary sources (Dunwoodie group publications and secondary press coverage) explicitly frame periconceptional niacin supplementation as a candidate primary-prevention strategy pending clinical validation.

13. Prevention

Primary prevention: The strongest candidate primary-prevention strategy is periconceptional/gestational niacin (vitamin B3) supplementation in couples known to carry pathogenic HAAO/KYNU/NADSYN1 variants, grounded directly in the mouse rescue data (Shi et al. 2017) — niacin enters the Preiss-Handler NAD⁺-synthesis pathway independently of the three affected de novo-pathway enzymes, restoring embryonic NAD⁺ sufficiency. This remains preclinically validated but not yet clinically proven or formally guideline-recommended in humans, and should be characterized in a KB entry as an emerging/hypothesis-level prevention strategy rather than an established standard of care.

Secondary prevention: Prenatal ultrasound surveillance in known at-risk pregnancies (both parents confirmed carriers) for early detection of cardiac, renal, and vertebral anomalies, enabling informed counseling about pregnancy management and coordinated perinatal/neonatal care planning.

Genetic counseling and reproductive options: Central to prevention in this AR disorder. GeneReviews recommends: confirming parental carrier status by molecular testing (also serving to distinguish true biparental inheritance from de novo variants, parental mosaicism, or uniparental disomy); offering carrier testing to reproductive partners of known carriers, especially where consanguinity is likely; and discussing prenatal diagnosis and preimplantation genetic testing (PGT) once the family's causal variants are known. For each pregnancy where both parents are confirmed carriers, recurrence risk is the standard AR figure: 25% affected, 50% carrier, 25% unaffected/non-carrier.

Public health/behavioral interventions: No population-level screening or public health program exists for this ultra-rare disorder; prevention efforts are necessarily family- and genetics-clinic-based rather than population-based.

Prophylaxis: As above, gestational niacin supplementation is the only biologically targeted prophylactic candidate under discussion in the literature, but is not yet an established prophylactic guideline.

14. Other Species / Natural Disease

Taxonomy of model organisms used: Mus musculus (NCBITaxon:10090) and Danio rerio (NCBITaxon:7955) — no naturally occurring veterinary/companion-animal disease analog has been reported in the literature reviewed (this is a laboratory-modeled human genetic disorder rather than a condition recognized in OMIA/veterinary case series).

Orthologous genes: Mouse Haao (MGI:1919711), Kynu (MGI ortholog), Nadsyn1 (MGI:1926164) are the direct murine orthologs used to generate the null-allele models; zebrafish orthologs (haao, kynu, nadsyn1) were used in the 2025 model.

Comparative biology: The kynurenine pathway and de novo NAD⁺ biosynthesis route are highly evolutionarily conserved from bacteria through vertebrates (noted explicitly in the KYNU/NAD-biosynthesis evolutionary literature), supporting cross-species mechanistic validity of the mouse and zebrafish models for this pathway, even though no spontaneous/natural veterinary disease counterpart is documented.

Zoonotic potential/transmission: Not applicable — this is a non-communicable genetic developmental disorder.

15. Model Organisms

Mouse (Mus musculus): - Genetic models: Haao-null and Kynu-null knockout mice (Shi et al. 2017, PMID: 28792876) are the foundational models establishing causality. - Phenotype recapitulation: Null mouse embryos develop malformations described as similar to those seen in affected human patients, attributed directly to embryonic NAD⁺ deficiency. - Key experimental result: Gestational niacin supplementation of null-mutant dams prevented malformations in their offspring — the single most important interventional proof-of-concept in the field, directly informing both mechanism (Section 6) and prevention hypotheses (Section 13). - Limitations: Mouse null models represent complete loss-of-function, which may not fully capture the phenotypic range seen with human hypomorphic/missense alleles (e.g., the milder NADSYN1 p.A573T genotype); litter-level variability and resorption patterns in these models have also been used (Mark 2022) to model human miscarriage risk, an extrapolation not yet directly validated in human tissue.

Zebrafish (Danio rerio): - A 2025 study (bioRxiv 10.1101/2025.01.10.632366; PMID: 39829932; also published in a peer-reviewed venue per ScienceDirect indexing) established the first zebrafish model of NAD⁺ deficiency-derived congenital disorders, targeting the same pathway genes, explicitly to further probe the unresolved question of why NAD⁺ deficiency selectively disrupts cardiac, renal, vertebral, and limb development and to test the hypothesis of shared mechanism with VACTERL association. - Applications: Zebrafish offer external embryonic development, rapid generation time, and amenability to high-throughput chemical/genetic screening — well suited to dissecting the still-open cell-signaling mechanism downstream of NAD⁺ depletion and to future compound (e.g., NAD⁺ precursor) screening.

Resources: MGI (Mouse Genome Informatics) for Haao/Kynu/Nadsyn1 mouse alleles; ZFIN for zebrafish CNDD-model lines as they become deposited; no dedicated patient-derived iPSC or organoid model of CNDD was identified in the literature reviewed, representing an additional experimental-model gap relative to many other monogenic disorders.

Summary Table: Key Evidence Citations

Claim	PMID	Citation
HAAO/KYNU cause CNDD; mouse niacin rescue	28792876	Shi et al. 2017, N Engl J Med 377:544–552
NADSYN1 (VCRL3) causal gene; severe lethal phenotype	31883644	Szot et al. 2020, Am J Hum Genet 106:129–136
KYNU hand hyperphalangism phenotype expansion	31923704	Ehmke et al. 2020, Bone
Expanded genotypic/phenotypic spectrum	33942433	Szot et al. 2021, Hum Mutat
Maternal chromosome 2 isodisomy/KYNU deletion	34200361	Schüle et al. 2021, Genes 12:879
Further NADSYN1 case description	35491967	Kortbawi et al. 2022, Am J Med Genet A
NADSYN1 clinical heterogeneity	36951206	Aubert-Mucca et al. 2023, Clin Genet
Oldest living patient (age 30); NAD level analysis	36649848	Erbs et al. 2023, Eur J Med Genet
Pleiotropy model linking CNDD to VACTERL/other spectra	35484986	Mark 2022, Am J Med Genet A 188:2834–2849
VACTERL differential diagnosis comparison	32596782	van de Putte et al. 2020
Single-variant NADSYN1 vertebral malformation	34681008	Lin et al. 2021, Genes
ACMG/AMP variant classification standard	25741868	Richards et al. 2015
Zebrafish CNDD model	39829932	2025, bioRxiv/peer-reviewed
GeneReviews comprehensive chapter	NBK593504	Adam MP et al. (eds.), "Congenital NAD Deficiency Disorder," updated July 2023

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	11
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	71
Resolved	63
Unresolved (possible confabulation)	0
Obsolete	2
Unverifiable	6
Terms whose name was checked	29
Terms named correctly	23
Terms named as a different term	3
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0002510 (1 mention) - the report calls it "One reported Lennox-Gastaut-type case"; HP calls it Spastic tetraplegia
GO:0034354 (1 mention) - the report calls it "NAD biosynthesis via nicotinamide riboside salvage pathway"; GO calls it 'de novo' NAD+ biosynthetic process from L-tryptophan
UBERON:0002298 (1 mention) - the report calls it "vertebral column"; UBERON calls it brainstem

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

HP:0001180 (obsolete Hand oligodactyly) (1 mention) - replaced by HP:0009380
GO:0043420 (obsolete anthranilate metabolic process) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0043420 (1 mention) - the report calls it "anthranilate metabolic process"; GO calls it obsolete anthranilate metabolic process, and lists "anthranilate catabolic process" among its other names
GO:0033721 (1 mention) - the report calls it "3-hydroxyanthranilate 3,4-dioxygenase activity"; GO calls it aldehyde dehydrogenase (NADP+) activity
GO:0006974 (1 mention) - the report calls it "cellular response to DNA damage stimulus, PARP-relevant"; GO calls it DNA damage response, and lists "cellular response to DNA damage stimulus" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

OpenScientist ▸

Congenital Vertebral-Cardiac-Renal Anomalies Syndrome — Comprehensive Disease Report

openscientist-autonomous 6 citations 2026-09-03T07:44:47.972693

Congenital Vertebral-Cardiac-Renal Anomalies Syndrome — Comprehensive Disease Report

Disease knowledge base entry — Mendelian congenital malformation syndrome

Summary

"Congenital Vertebral-Cardiac-Renal Anomalies Syndrome" is Congenital NAD Deficiency Disorder (CNDD), also catalogued as Vertebral, Cardiac, Renal and Limb Defects Syndrome (VCRL). It is an autosomal-recessive inborn error of de novo nicotinamide adenine dinucleotide (NAD) biosynthesis. The disorder is caused by biallelic loss-of-function variants in one of three genes encoding sequential enzymes of the kynurenine (tryptophan → NAD) pathway: HAAO (3-hydroxyanthranilate 3,4-dioxygenase; VCRL1, OMIM #617660), KYNU (kynureninase; VCRL2, OMIM #617661), and NADSYN1 (NAD synthetase 1; VCRL3, OMIM #618845). The unifying biochemical lesion is a deficiency of NAD during embryogenesis, which disrupts organogenesis of the vertebrae, heart, kidneys and limbs, producing a phenotype that overlaps heavily with the VACTERL/VATER association.

The mechanistic story of this disorder is unusually complete for a rare Mendelian condition, and it is remarkable for one reason: the malformations are, in principle, preventable. In Haao-null and Kynu-null mouse embryos, defects mirroring those of patients arise directly from NAD deficiency, and gestational supplementation with niacin/nicotinamide (NAD precursors) prevents them. The causal network extends beyond the three core enzymes: environmental NAD deprivation (maternal dietary vitamin B3/tryptophan restriction, hypoxia) and maternal modifier genotypes — notably heterozygosity for the tryptophan transporter gene SLC6A19 (B0AT1) — can independently lower embryonic NAD and reproduce the malformation spectrum, establishing a genuine maternal–fetal, gene–environment axis.

The syndrome shows variable expressivity. The classic severe presentation (HAAO/KYNU) includes renal anomalies and can be lethal, but NADSYN1-associated CNDD can spare the kidneys and limbs, fail to meet formal VACTERL criteria, and be compatible with survival into adulthood. Because each causal gene occupies a distinct enzymatic step, patients carry gene-specific plasma metabolite signatures (accumulation of the substrate upstream of the blocked enzyme with low downstream NAD), which offers a functional-biochemical diagnostic strategy complementing genomic sequencing. This report consolidates the identity, etiology, phenotypes, molecular genetics, mechanism, anatomy, temporal course, epidemiology, diagnostics, prognosis, treatment, prevention, and model-organism evidence for the disorder.

1. Disease Information

Overview. Congenital NAD Deficiency Disorder (CNDD) / VCRL is a multiple-congenital-malformation syndrome resulting from insufficient NAD during embryonic development. NAD is an essential redox cofactor and signaling substrate; when its synthesis is impaired during organogenesis, multiple organ systems that require high NAD flux — the developing axial skeleton, heart, kidney/urinary tract and limbs — form abnormally. Clinically the disorder presents within the VACTERL/VATER spectrum (Vertebral defects, Anal atresia, Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities), and CNDD should be considered a molecularly-defined, recessive cause of VACTERL-like presentations.

Key identifiers.

Resource	Identifier
Disease term	Congenital NAD Deficiency Disorder (CNDD)
Synonym	Vertebral, Cardiac, Renal and Limb Defects Syndrome (VCRL)
OMIM (HAAO)	VCRL1 #617660
OMIM (KYNU)	VCRL2 #617661
OMIM (NADSYN1)	VCRL3 #618845
MONDO	Not assigned in the provided evidence; map to the VCRL/CNDD grouping when available
Category	Mendelian, autosomal recessive

Synonyms / alternative names: Congenital NAD Deficiency Disorder; VCRL syndrome; Vertebral, Cardiac, Renal and Limb Defects Syndrome; VACTERL-like NAD-deficiency malformation syndrome. The term "Congenital Vertebral-Cardiac-Renal Anomalies Syndrome" used in the research template is a descriptive alias for this entity.

Information source. The evidence base is a mixture of individual patient reports/case series (human clinical genetics) and aggregated disease-level resources (OMIM gene-disease designations), supplemented heavily by model-organism (mouse) experiments that establish causality.

Supporting evidence — NAD Deficiency, Congenital Malformations, and Niacin Supplementation PMID: 28792876: "Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU)."

New cases that expand the genotypic and phenotypic spectrum of Congenital NAD Deficiency Disorder PMID: 33942433: "Biallelic, inactivating variants in three genes encoding enzymes of this biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder."

2. Etiology

Primary causal factors — genetic. CNDD is caused by biallelic (homozygous or compound-heterozygous) loss-of-function variants in HAAO, KYNU, or NADSYN1. The foundational study identified homozygous HAAO p.D162* and HAAO p.W186*, KYNU p.V57Efs*21, and compound-heterozygous KYNU p.Y156*/p.F349Kfs*4; the encoded enzymes had greatly reduced in vitro activity, and patients had reduced circulating NAD [PMID: 28792876]. Subsequent work added NADSYN1 as the third causal gene [PMID: 33942433].

Primary causal factor — biochemical. The convergent mechanism is NAD deficiency during embryogenesis. Whether the block is upstream (KYNU, HAAO) or terminal (NADSYN1), the result is inadequate NAD for the metabolic demands of organogenesis.

Genetic risk factors. Causal variants are the three-gene set above. Maternal modifier genotype is an additional risk axis: maternal heterozygosity for SLC6A19 (B0AT1, the neutral amino-acid/tryptophan transporter) can precipitate CNDD in offspring when NAD precursor supply is limited [PMID: 36374036].

Environmental risk factors. NAD deficiency of environmental origin — maternal dietary deficiency of vitamin B3 (niacin) and/or tryptophan, and hypoxia — causes congenital malformations and miscarriage in mice [PMID: 32015132]. These act on the same NAD-supply bottleneck as the genetic lesions.

Protective factors. The dominant protective factor is adequate maternal dietary NAD precursor supply (niacin/nicotinamide, dietary tryptophan). In genetic mouse models, precursor supplementation prevents the malformations [PMID: 28792876]. No specific protective human genetic alleles are established in the provided evidence.

Gene–environment interaction. CNDD is a paradigm of gene–environment interaction: a partially compromised genetic NAD-synthesis capacity (e.g., maternal Slc6a19 heterozygosity, or hypomorphic pathway alleles) becomes pathogenic only when environmental precursor supply is insufficient. "NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice" [PMID: 32015132].

Supporting evidence — PMID: 36374036: "This perturbed the NAD metabolome in pregnant Slc6a19+/- females, resulting in reduced NAD levels and increased rates of embryo loss." … "They also suggest that human female carriers of a SLC6A19 loss-of-function allele might be susceptible to adverse pregnancy outcomes unless sufficient NAD precursor amounts are available during gestation."

3. Phenotypes

CNDD is a multiple-malformation syndrome with a core tetrad of vertebral, cardiac, renal, and limb anomalies and additional craniofacial and developmental features. Phenotypes are congenital (present at birth) and represent fixed structural malformations (physical manifestations / clinical signs), not progressive or episodic symptoms; developmental delay is an additional feature in survivors. Severity is variable, ranging from prenatal/neonatal lethality to adult survival.

Phenotype	Type	Onset	Frequency / notes	Suggested HPO
Vertebral segmentation defects (hemivertebrae, spinal segmentation anomalies)	Skeletal malformation	Congenital	Core feature; present across genes	HP:0000925 (Abnormality of the vertebral column); HP:0008438 (Abnormal vertebral segmentation)
Rib anomalies	Skeletal malformation	Congenital	Reported (e.g., adult NADSYN1 case)	HP:0000772 (Abnormal rib morphology)
Congenital heart defects (incl. HLHS, aortic coarctation, transverse aortic arch hypoplasia, bicuspid aortic valve stenosis)	Cardiovascular malformation	Congenital	Core feature; severe lesions reported with NADSYN1	HP:0001627 (Abnormal heart morphology); HP:0004421 (VSD); HP:0004383 (Hypoplastic left heart)
Renal / urinary tract anomalies	Genitourinary malformation	Congenital	Core in HAAO/KYNU; spared in some NADSYN1 cases	HP:0000077 (Abnormality of the kidney); HP:0000107 (Renal cyst)
Limb anomalies (incl. unequal leg length)	Skeletal malformation	Congenital	Core in classic cases; may be absent in NADSYN1	HP:0002813 (Abnormality of limb bone morphology)
Cleft palate	Craniofacial malformation	Congenital	Reported in NADSYN1	HP:0000175 (Cleft palate)
Ptosis	Craniofacial/ocular	Congenital	Reported in adult NADSYN1	HP:0000508 (Ptosis)
Developmental delay	Neurodevelopmental	Childhood	In some surviving patients	HP:0001263 (Global developmental delay)
Reduced circulating NAD	Laboratory abnormality	Congenital/lifelong	Biochemical hallmark	—

Quality-of-life impact. Depends on organ severity: severe cardiac and renal malformations drive early morbidity/mortality and require major surgical intervention; skeletal defects cause chronic orthopedic disability (e.g., unequal leg length, spinal deformity); developmental delay affects long-term function. Formal EQ-5D/SF-36 data are not available for this ultra-rare disorder.

4. Genetic / Molecular Information

Causal genes (three-gene locus heterogeneity).

Gene	Protein / enzyme	Pathway step	OMIM disease	Representative variants
HAAO	3-hydroxyanthranilate 3,4-dioxygenase	3-HAA → ACMS (upstream)	VCRL1 #617660	p.D162, p.W186 (homozygous nonsense); homozygous exon-5 deletion reported
KYNU	Kynureninase	3-hydroxykynurenine → 3-HAA (upstream)	VCRL2 #617661	p.V57Efs21 (homozygous); p.Y156/p.F349Kfs*4 (compound het)
NADSYN1	NAD synthetase 1	NaAD → NAD, terminal amidation (downstream)	VCRL3 #618845	c.1717G>A p.Ala573Thr (homozygous, adult case); compound-het variants in cardiac/vertebral cases

Variant classification & type. Reported variants are predominantly nonsense, frameshift, and structural (whole-exon deletion) loss-of-function alleles, classified pathogenic/likely pathogenic under ACMG/AMP criteria (null variants in genes with an established LoF mechanism, functionally validated by reduced enzyme activity). At least one missense allele (NADSYN1 p.Ala573Thr) is associated with a milder, adult-surviving phenotype.

Functional consequence. Loss of function — reduced or abolished enzyme activity impairing de novo NAD synthesis. The foundational study confirmed "greatly reduced" activity by in vitro enzyme assays [PMID: 28792876].

Allele frequency / origin. Pathogenic alleles are rare; the disorder is recessive and consanguinity-associated (homozygous null alleles). All reported disease variants are germline; there is no somatic component.

Modifier genes. SLC6A19 (maternal B0AT1 tryptophan transporter) acts as a maternal modifier/risk gene by limiting substrate for the tryptophan→NAD pathway [PMID: 36374036]. Additional NAD-pathway and transporter genes are plausible modifiers.

Epigenetic / chromosomal information. No specific disease-defining epigenetic signature or recurrent chromosomal abnormality is established. One reported HAAO lesion is a homozygous exon-5 deletion, detectable by copy-number/structural methods.

5. Environmental Information

Environmental factors: Maternal hypoxia and dietary vitamin B3 (niacin) / tryptophan deficiency lower embryonic NAD and cause malformations and miscarriage in mice [PMID: 32015132]. These environmental insults phenocopy the genetic disorder.
Lifestyle factors: Maternal nutrition during pregnancy — adequacy of niacin and tryptophan intake — is the key modifiable lifestyle determinant.
Infectious agents: Not applicable. CNDD is not an infectious disease.

6. Mechanism / Pathophysiology

Ordered causal chain

A biallelic loss-of-function variant in HAAO, KYNU, or NADSYN1 (or a maternal modifier such as SLC6A19 heterozygosity, and/or environmental precursor deprivation) reduces the activity of a kynurenine-pathway enzyme → leads to a block in de novo NAD biosynthesis.
The enzymatic block results in accumulation of the upstream substrate (gene-specific) and a fall in downstream NAD.
Reduced availability of maternal-fetal NAD precursors compounds the deficit (branch: the environmental/gene–environment route can initiate the same lesion independently of the three core genes).
NAD deficiency in the embryo during the critical window of organogenesis results in impaired NAD-dependent cellular processes (redox metabolism, ADP-ribosylation/PARP signaling, sirtuin activity) — the precise downstream molecular effectors in affected tissues are inferred rather than fully demonstrated.
Impaired NAD-dependent processes in progenitor tissues disrupt normal morphogenesis of the somites/vertebrae, cardiac outflow and chambers, nephrogenic mesenchyme, and limb buds → leads to the structural malformations.
The malformations manifest clinically as vertebral segmentation defects, congenital heart disease, renal/urinary anomalies, and limb defects (with variable craniofacial involvement) — and, when NAD deficiency is severe, result in embryo loss/miscarriage.

LoF variant (HAAO / KYNU / NADSYN1)      Maternal SLC6A19+/-  +  low niacin/Trp  or  hypoxia
|                                             |
v                                             v
  Block in de novo NAD synthesis  <-------------------+
|
v
  Upstream substrate accumulates  +  NAD pool falls
|
v
  NAD-dependent processes impaired in embryo (inferred effectors)
|
+--> Somite/vertebral morphogenesis disrupted --> vertebral defects
+--> Cardiac morphogenesis disrupted -----------> CHD (HLHS, CoA, BAV)
+--> Nephrogenesis disrupted -------------------> renal/urinary anomalies
+--> Limb-bud patterning disrupted -------------> limb defects
+--> Severe deficiency -------------------------> embryo loss / miscarriage

Pathway detail

Molecular pathway: The kynurenine (tryptophan → NAD) de novo biosynthesis pathway. Order: tryptophan → … → 3-hydroxykynurenine → (KYNU) → 3-hydroxyanthranilic acid → (HAAO) → ACMS → … → nicotinic acid adenine dinucleotide (NaAD) → (NADSYN1) → NAD. NADSYN1 catalyzes the terminal amidation step, which is shared with the Preiss–Handler pathway, explaining partial salvage rescue (see below) [PMID: 28792876; PMID: 36649848].
Cellular processes: NAD is required for redox reactions, PARP-mediated DNA repair/signaling, and sirtuin-dependent regulation; its depletion in rapidly proliferating embryonic progenitors is the presumed proximate cellular lesion.
Protein dysfunction: Loss of enzymatic function (null/hypomorphic), with reduced in vitro activity confirmed [PMID: 28792876].
Metabolic changes: Reduced circulating and tissue NAD; gene-specific accumulation of pathway intermediates.
Biomarker corollary (Finding F005): Because each enzyme sits at a distinct step, expected plasma signatures are — KYNU deficiency: kynurenine / 3-hydroxykynurenine (with shunting to xanthurenic/kynurenic acid); HAAO deficiency: 3-hydroxyanthranilic acid; NADSYN1 deficiency: NaAD — each accompanied by low NAD.
Salvage-pathway rescue: NADSYN1's terminal position allows partial NAD replenishment via nicotinamide/salvage: in an adult patient "the NAD pool rose approximately 25% after supplementation with nicotinamide" [PMID: 36649848].

Suggested ontology terms: GO:0009435 (NAD biosynthetic process); GO:0034354 (de novo NAD biosynthetic process from tryptophan); GO:0043420 (anthranilate metabolic process); GO:0006979 (response to oxidative stress). Cell types (CL): CL:0000222 (mesodermal cell), somite/sclerotome progenitors, cardiac progenitor cells, metanephric mesenchymal cells, limb mesenchyme.

Supporting evidence — PMID: 28792876: "Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency." … "We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma."

7. Anatomical Structures Affected

Organ level (primary): vertebral column / axial skeleton (UBERON:0001130 vertebral column), heart (UBERON:0000948), kidney (UBERON:0002113) and urinary tract, limbs (UBERON:0002101). Additional: palate (UBERON:0001716), ribs (UBERON:0002228), eyelid (ptosis).

Body systems: cardiovascular, skeletal/musculoskeletal, genitourinary/renal, and (variably) craniofacial and central nervous (developmental delay).

Secondary involvement: complications of the primary malformations — heart failure and cyanosis from CHD; renal insufficiency from urinary tract anomalies; orthopedic sequelae (scoliosis, limb-length discrepancy).

Tissue/cell level: predominantly mesodermally-derived progenitor tissues — sclerotome/somite (vertebrae), cardiac mesoderm/neural-crest-derived outflow structures, nephrogenic (metanephric) mesenchyme, and limb-bud mesenchyme. Cell Ontology suggestions: CL:0000222 (mesodermal cell); cardiac progenitor cell; metanephric mesenchyme cell; limb mesenchymal cell.

Subcellular level: NAD metabolism spans cytosol and mitochondria; relevant GO cellular components include GO:0005739 (mitochondrion) and GO:0005829 (cytosol). The enzymatic steps of the kynurenine pathway are cytosolic, while NAD-dependent energy metabolism is heavily mitochondrial.

Localization / lateralization: Malformations are typically bilateral or midline/axial (vertebrae, heart, palate), though specific cardiac lesions (e.g., aortic arch anomalies, HLHS) reflect left-sided/outflow structures.

8. Temporal Development

Onset: Congenital / prenatal. The malformations arise during embryonic organogenesis; the most severe cases present as prenatal loss/miscarriage or neonatal death. The insult window is the critical period of somite, cardiac, renal, and limb morphogenesis.
Onset pattern: Fixed structural malformations established in utero (not acute/insidious postnatal onset).
Progression / course: The malformations themselves are static (non-progressive) structural defects, but their complications are progressive (e.g., heart failure, renal insufficiency, orthopedic deformity). Disease is chronic and lifelong in survivors.
Disease stages: Best framed as (i) prenatal establishment of malformations, (ii) neonatal/perinatal presentation and stabilization, (iii) childhood surgical correction and developmental follow-up, (iv) long-term management of residual disability. Some patients survive to adulthood (NADSYN1 case at age 30) [PMID: 36649848].
Critical period / window of opportunity: Preconception and early gestation — the only demonstrated point of effective intervention is ensuring adequate NAD precursor supply before and during organogenesis (see Prevention).

9. Inheritance and Population

Inheritance pattern: Autosomal recessive. Disease requires biallelic LoF variants; heterozygous carriers are generally unaffected (though maternal carrier genotype at SLC6A19 can, under precursor limitation, contribute to offspring risk — a maternal-effect/gene–environment nuance).
Penetrance / expressivity: Variable expressivity is prominent. The classic HAAO/KYNU presentation includes renal and limb anomalies and can be lethal; NADSYN1 cases can spare the kidneys and limbs, not meet VACTERL criteria, and survive to adulthood [PMID: 35491967; PMID: 36649848]. Environmental precursor supply modulates penetrance.
Consanguinity: Homozygous null alleles in reported families indicate a role for consanguinity/founder recessive inheritance; specific founder alleles are not established in the provided evidence.
Anticipation / mosaicism: Not applicable (no repeat-expansion mechanism); germline mosaicism not reported.
Epidemiology: CNDD is ultra-rare, with only a small number of families/cases reported worldwide since 2017; precise prevalence/incidence figures are not established. The condition is likely under-ascertained, because milder (renal-sparing, adult-surviving) presentations may not be recognized or genetically tested [PMID: 35491967].
Sex ratio / demographics: No strong sex bias expected for an autosomal recessive malformation syndrome; specific ethnic/geographic clustering is undefined beyond consanguineous pedigrees.

10. Diagnostics

Genetic testing (primary diagnostic modality). - Whole-exome (WES) or whole-genome sequencing (WGS) is the cornerstone, identifying biallelic LoF variants in HAAO, KYNU, or NADSYN1. Trio sequencing aids phasing (compound heterozygosity). - Targeted gene panels covering HAAO / KYNU / NADSYN1 (and NAD-pathway genes) are appropriate for VACTERL-like presentations. - Chromosomal microarray / copy-number analysis is needed to detect structural alleles (e.g., the reported homozygous HAAO exon-5 deletion). - Actionable recommendation: NADSYN1 sequencing should be performed in children with VATER/VACTERL-related anomalies and in those with HLHS or aortic arch abnormalities [PMID: 35491967].

Biochemical / metabolomic testing (functional confirmation). - Plasma NAD quantification (reduced) and targeted kynurenine-pathway metabolomics provide functional evidence and can localize the defect to a specific enzymatic step (gene-specific substrate accumulation with low NAD) [PMID: 28792876]. This is especially useful to classify variants of uncertain significance.

Imaging & clinical work-up. - Echocardiography / cardiac imaging for CHD; spine and skeletal radiographs / CT for vertebral and rib anomalies; renal ultrasound for urinary tract malformation; prenatal ultrasound/fetal echo can detect malformations in utero.

Clinical criteria / differential diagnosis. - Presentations overlap the VACTERL/VATER association; CNDD is a specific molecular subtype. Differential diagnoses include other VACTERL-like syndromes, chromosomal disorders, TBX-pathway and ciliopathy-related malformation syndromes, and teratogen-induced malformations. The distinguishing features of CNDD are recessive inheritance, biallelic NAD-pathway gene variants, low NAD, and abnormal kynurenine metabolites.

Screening. Carrier screening in consanguineous families and cascade testing of relatives once a proband variant is identified.

11. Outcome / Prognosis

Survival / mortality: Highly variable and organ-severity dependent. Severe cardiac (e.g., HLHS) and renal malformations, or profound embryonic NAD deficiency, cause prenatal loss, neonatal death, or high early mortality. Milder (renal-sparing) NADSYN1 disease is compatible with survival to adulthood (documented case at age 30) [PMID: 36649848].
Morbidity / disability: Chronic disability from congenital heart disease, renal insufficiency, spinal/skeletal deformity (scoliosis, limb-length discrepancy), and developmental delay in some survivors.
Complications: Heart failure, cyanosis, arrhythmia post-repair; chronic kidney disease; orthopedic sequelae; feeding/growth issues with cleft palate.
Recovery potential: Structural malformations do not resolve but are surgically correctable (e.g., bicuspid aortic valve stenosis corrected surgically in the adult NADSYN1 case) [PMID: 36649848]; prognosis improves with early surgical management.
Prognostic factors: Causal gene and residual enzyme activity, severity of cardiac and renal lesions, degree of NAD deficiency, and adequacy of any perinatal NAD precursor supply.

12. Treatment

CNDD malformations are structural and established prenatally, so postnatal treatment is corrective/supportive, while the disorder's landmark feature is a preventive metabolic intervention (see Section 13).

Metabolic/pharmacologic (NAD precursors): Niacin/nicotinamide (vitamin B3) supplementation is the mechanistically-targeted therapy. Its principal value is preventive during gestation; postnatally it can partly replenish the NAD pool, particularly in NADSYN1 disease where the salvage pathway bypasses the terminal defect — nicotinamide raised the NAD pool ~25% in an adult NADSYN1 patient [PMID: 36649848]. CHEBI: nicotinamide (CHEBI:17154), nicotinic acid/niacin (CHEBI:15940), NAD (CHEBI:15846). NCIT: Niacin/Nicotinamide therapy.
Surgical / interventional: Repair of congenital heart defects (e.g., aortic valve/arch surgery, HLHS staged palliation), urologic/renal surgery, and orthopedic correction of spinal and limb anomalies.
Supportive / rehabilitative: Cardiology and nephrology management, physical/occupational therapy for skeletal disability, developmental support and early intervention, nutritional support (especially with cleft palate).
Personalized medicine: Genotype-guided — NADSYN1 (terminal step) patients are the most likely to derive biochemical benefit from salvage-pathway precursors (nicotinamide/nicotinamide riboside).
Experimental / trials: No disease-specific approved therapeutics or registered trials are identified in the provided evidence; NAD-precursor supplementation is the leading translational strategy.

13. Prevention

Prevention is the defining, most impactful aspect of this disorder.

Primary prevention (the key intervention): Ensure adequate maternal NAD precursor status (niacin/nicotinamide, dietary tryptophan) before conception and throughout gestation. In genetic mouse models, gestational supplementation prevents the malformations: "Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency" — and were prevented by supplementation [PMID: 28792876]. Environmental/gene–environment NAD deficiency causing malformations is likewise precursor-preventable [PMID: 32015132].
High-risk targeting: Maternal carriers of SLC6A19 LoF alleles (and couples with a prior CNDD child) are candidates for precursor supplementation and close pregnancy monitoring [PMID: 36374036].
Secondary prevention: Prenatal ultrasound/fetal echocardiography and early postnatal imaging for early detection and surgical planning.
Genetic counseling: For autosomal-recessive recurrence risk (25% for carrier couples), carrier and cascade testing, and reproductive options (prenatal diagnosis, PGT). Counsel carrier mothers about NAD precursor adequacy in future pregnancies.
Public health corollary: Adequate maternal niacin/tryptophan nutrition is a broadly protective, low-cost measure against NAD-deficiency malformations.

Supporting evidence — PMID: 32015132: "NAD deficiency due to environmental factors or gene-environment interactions causes congenital malformations and miscarriage in mice."

14. Other Species / Natural Disease

Taxonomy / models: Demonstrated in mouse (Mus musculus, NCBI:txid10090). No naturally-occurring companion-animal or wildlife CNDD equivalent is documented in the provided evidence.
Orthologous genes: Haao, Kynu, Nadsyn1, and Slc6a19 are conserved in mouse and other mammals; the kynurenine→NAD pathway is evolutionarily conserved, supporting cross-species mechanistic translation.
Comparative biology: Mouse knockouts recapitulate the human malformation spectrum via NAD deficiency, indicating strong evolutionary conservation of the disease mechanism [PMID: 28792876; PMID: 32015132].
Zoonotic potential: None (non-infectious genetic/metabolic disorder).

15. Model Organisms

Primary model — mouse: Haao-null and Kynu-null mice develop malformations mirroring patients due to NAD deficiency, and these are prevented by gestational niacin/nicotinamide [PMID: 28792876]. This model demonstrates causality and the preventive intervention.
Environmental/gene–environment model: Mice exposed to maternal vitamin B3/tryptophan restriction or hypoxia, and maternal Slc6a19+/− mice on B3-depleted diets, develop reduced NAD, increased embryo loss, and CNDD-type malformations [PMID: 32015132; PMID: 36374036].
Phenotype recapitulation: High — mouse models reproduce the vertebral/cardiac/renal/limb malformation spectrum and the NAD-deficiency biochemistry, and validate the preventive strategy.
Model limitations: Human genotype–phenotype variability (e.g., renal-sparing NADSYN1 adults) and specific severe cardiac lesions (HLHS) are not fully captured; timing/dose thresholds of NAD deficiency versus specific malformations require further definition.
Model type suggestions for future work: Conditional/tissue-specific NAD-pathway knockouts; NADSYN1 hypomorph knock-in models; patient-iPSC–derived cardiac/renal organoids to model gene-specific metabolite signatures and precursor rescue.

Mechanistic Model / Interpretation

CNDD is best understood as a single convergent metabolic bottleneck (embryonic NAD supply) reached by multiple routes. The three core genes map to distinct, sequential steps of the de novo pathway; a block at any step lowers NAD. Crucially, the terminal position of NADSYN1 — shared with the Preiss–Handler/salvage route — explains two clinical observations: (1) NADSYN1 disease can be milder/renal-sparing and adult-compatible, and (2) it is the genotype most amenable to salvage-pathway rescue with nicotinamide (~25% NAD pool increase). Meanwhile, the maternal–fetal supply network (dietary niacin/tryptophan, hypoxia, maternal SLC6A19 transporter genotype) can push embryonic NAD below the morphogenetic threshold even without biallelic core-gene lesions, making CNDD a textbook gene–environment disorder. The therapeutic and preventive corollary is unusually clear for a Mendelian malformation syndrome: guarantee NAD precursor supply during the periconceptional/early-gestational critical window.

Gene	Step	Expected accumulated metabolite	NAD	Typical severity
KYNU	3-OH-kynurenine → 3-HAA (upstream)	kynurenine / 3-OH-kynurenine (± xanthurenic/kynurenic acid)	Low	Classic severe, renal-inclusive
HAAO	3-HAA → ACMS (upstream)	3-hydroxyanthranilic acid	Low	Classic severe, renal-inclusive
NADSYN1	NaAD → NAD (terminal)	nicotinic acid adenine dinucleotide (NaAD)	Low	Variable; can spare kidney/limb; salvage-rescuable

Evidence Base

PMID	Title (abbrev.)	Role in this report
28792876	NAD Deficiency, Congenital Malformations, and Niacin Supplementation	Foundational: identifies HAAO/KYNU variants, reduced NAD, mouse causality, prevention by niacin
33942433	New cases that expand the genotypic and phenotypic spectrum of CNDD	Names the three causal genes (KYNU, HAAO, NADSYN1) and the disease term/phenotype
35491967	Two patients with biallelic NADSYN1 variants (cardiac and vertebral anomalies)	Documents renal/limb-sparing NADSYN1 phenotype, HLHS/aortic arch link, testing recommendation
36649848	Adult patient with NADSYN1-associated congenital NAD deficiency	Adult survival, renal sparing, ~25% NAD rise with nicotinamide (salvage rescue)
32015132	NAD deficiency from environmental factors/gene-environment interactions in mice	Establishes environmental & GxE routes to the malformation phenotype
36374036	Maternal heterozygosity of Slc6a19 causes CNDD in mice	Maternal modifier/gene–environment axis; carrier-risk implication
37300479	NAD Deficiency and Its Impact on Mammalian Development (review)	Consolidating review of NAD in development
34681008	Disruptive [NAD pathway variants]	Additional evidence on NAD-pathway perturbation and birth defects
34200361	Homozygous deletion of exon 5 of [HAAO], VCRL syndrome	Structural (exon-deletion) allele; VCRL nomenclature

Note on a citation caveat: The knowledge outline flags the PMID 32015132 snippet as a "mismatch" during verification; the quoted sentence should be treated as paraphrasing the paper's demonstrated conclusion (environmental/GxE NAD deficiency causing malformations/miscarriage in mice) rather than an exact-verified verbatim quote. All other quoted snippets in this report were verified against stored abstracts.

Limitations and Knowledge Gaps

Rarity and ascertainment: Only a small number of families/cases are reported; true prevalence, incidence, penetrance, and sex/geographic distribution are unknown. Milder (renal-sparing, adult-surviving) cases are likely under-diagnosed [PMID: 35491967].
Downstream molecular effectors are inferred: The exact NAD-dependent processes (PARP, sirtuin, redox) linking NAD deficiency to specific malformations in specific tissues are not fully demonstrated in human tissue.
No formal MONDO ID captured in the evidence set; database harmonization (MONDO/Orphanet/ICD-11 mapping) is incomplete here.
Biomarker signatures are predicted, not fully clinically validated: Gene-specific plasma metabolite panels are mechanistically expected but require prospective diagnostic validation.
Treatment evidence is preclinical/anecdotal: Prevention efficacy is established in mice; human dosing, timing, and outcome data (especially preventive supplementation in at-risk pregnancies) are lacking. The ~25% NAD rise with nicotinamide is a single adult case.
No QoL, survival-curve, or registry data exist for this ultra-rare disorder.

Proposed Follow-up Experiments / Actions

Establish a CNDD patient registry across HAAO/KYNU/NADSYN1 genotypes to define natural history, penetrance, expressivity, survival, and genotype–phenotype correlations.
Validate gene-specific plasma metabolite diagnostics (kynurenine, 3-OH-kynurenine, 3-hydroxyanthranilic acid, NaAD, NAD) as a functional test to resolve VUS and localize the enzymatic block.
Prospective preventive-supplementation study of NAD precursors in high-risk pregnancies (prior affected child; maternal SLC6A19 or NAD-pathway carriers), building on mouse prevention data [PMID: 28792876; PMID: 36374036].
Define maternal SLC6A19 and NAD-pathway carrier frequencies in populations and evaluate periconceptional NAD status as an adverse-pregnancy-outcome risk marker.
Model organism dissection of the critical window: conditional NAD-pathway knockouts and iPSC-derived cardiac/renal/somite organoids to map NAD thresholds, timing, and the downstream effectors (PARP/sirtuin/redox) per organ.
Assess NADSYN1 salvage-rescue therapeutically: trial nicotinamide/nicotinamide riboside in NADSYN1 patients with biochemical endpoints (NAD pool) and clinical follow-up.
Formal ontology harmonization: assign/confirm MONDO, Orphanet, ICD-11, and MeSH mappings and align HPO annotation frequencies with registry data.

Evidence source types used: human clinical genetics (case reports/series), aggregated disease resources (OMIM), and model-organism (mouse) experiments, with mechanistic inference where noted.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	9
On topic	9
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	28
Resolved	27
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	0
Terms whose name was checked	12
Terms named correctly	9
Terms named as a different term	0
Terms whose name is worth a second look	3

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0043420 (obsolete anthranilate metabolic process) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002813 (1 mention) - the report calls it "Abnormality of limb bone morphology"; HP calls it Abnormal limb bone morphology, and lists "Abnormality of limb bone morphology" among its other names
GO:0034354 (1 mention) - the report calls it "de novo NAD biosynthetic process from tryptophan"; GO calls it 'de novo' NAD+ biosynthetic process from L-tryptophan*, and lists "'de novo' NAD biosynthetic process from tryptophan" among its other names
GO:0043420 (1 mention) - the report calls it "anthranilate metabolic process"; GO calls it obsolete anthranilate metabolic process, and lists "anthranilate catabolic process" among its other names

27 of 28 terms resolved to a current term; the rest could not be looked up either way.

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Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Prevalence

Clinical Burden

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table: Key Evidence Citations

Sources

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Prefixes with no resolver

Congenital Vertebral-Cardiac-Renal Anomalies Syndrome — Comprehensive Disease Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Pathway detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Obsolete terms

Terms whose name is worth a second look