SHILCA Syndrome

Mendelian MONDO:0031007 Pathograph 21 Show in embeddings browser NMNAT1-related retinopathy Leber congenital amaurosis Spondyloepiphyseal dysplasia

SHILCA syndrome is an autosomal recessive multisystem disorder caused by biallelic NMNAT1 alleles that reduce expression of the nuclear NAD+ synthase more severely than the alleles behind retina-restricted Leber congenital amaurosis 9. The defining features are a severe spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis, with brain anomalies on MRI. The one compound heterozygous patient described in detail also had severe short stature, hypomyelinating leukoencephalopathy, progressive brain and cerebellar atrophy, corpus callosum hypoplasia and pseudocolobomatous macular atrophy. Every reported patient carries an Alu-mediated duplication of NMNAT1 exons 4-5 on a shared founder haplotype, either homozygous or in trans with a splice variant. The duplication cuts NMNAT1 expression roughly four-fold and produces aberrant transcripts. Complete loss of Nmnat1 is embryonic lethal in mice, so the authors read SHILCA as the intermediate point on an NMNAT1 dosage series between LCA9 and lethality. That extra-retinal tissues fail because nuclear NAD+ falls below what they tolerate is a hypothesis; NAD+ has not been measured in patients. Four patients are published.

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Inheritance

1
Autosomal recessive inheritance HP:0000007
Homozygous NMNAT1 exon 4-5 duplication in three Italian children from two families, and compound heterozygosity for the same duplication with a paternally inherited splice variant in one Spanish child.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:32533184 SUPPORT Human clinical
"presenting with a previously unrecognized autosomal recessive disorder"
The index report describes the disorder as autosomal recessive.
PMID:32533184 SUPPORT Human clinical
"Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype."
The affected children share an autozygous NMNAT1-containing interval, consistent with recessive inheritance.
PMID:33668384 SUPPORT Human clinical
"Thus, the splicing mutation and the duplication detected in the patient were present in heteroallelic combination, in accordance with the proposed inheritance pattern and the familial history"
Compound heterozygosity with parental segregation in a second family.
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Mechanistic Hypotheses

1
Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
nmnat1_extraretinal_nad_threshold EMERGING
Evidence balance 2 support
The SHILCA alleles leave less NMNAT1 than LCA9 alleles do, and complete loss is embryonic lethal in mice. The proposal is that skeletal, cochlear and brain tissue tolerate the LCA9 reduction but not the SHILCA one. Neither NAD+ levels nor any tissue-specific step has been measured in patients or in a model carrying SHILCA alleles.
Pathograph links
Multi-Tissue Nuclear NAD+ Insufficiency -> Spondyloepiphyseal Dysplasia INDIRECT UNKNOWN INTERMEDIATES Hypothesized; no study links NAD+ shortfall to the growth plate.
Multi-Tissue Nuclear NAD+ Insufficiency -> Sensorineural Hearing Loss INDIRECT UNKNOWN INTERMEDIATES Hypothesized; the cochlear cell type and mechanism are unstudied.
Multi-Tissue Nuclear NAD+ Insufficiency -> CNS Hypomyelination INDIRECT UNKNOWN INTERMEDIATES Hypothesized; oligodendrocyte NAD+ has not been studied in this disorder.
Multi-Tissue Nuclear NAD+ Insufficiency -> Intellectual Disability INDIRECT UNKNOWN INTERMEDIATES Hypothesized; no neuronal mechanism has been studied.
Multi-Tissue Nuclear NAD+ Insufficiency -> Global Developmental Delay INDIRECT UNKNOWN INTERMEDIATES Hypothesized; no neuronal mechanism has been studied.
Multi-Tissue Nuclear NAD+ Insufficiency -> Brain Atrophy INDIRECT UNKNOWN INTERMEDIATES Hypothesized; reported in one patient only.
Multi-Tissue Nuclear NAD+ Insufficiency -> Cerebellar Atrophy INDIRECT UNKNOWN INTERMEDIATES Hypothesized; reported in one patient only.
Show evidence (2 references)
PMID:32533184 SUPPORT INDIRECT Human clinical
"The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality."
The authors' own dosage proposal.
PMID:22842230 SUPPORT Human clinical
"All individuals with biallelic NMNAT1 mutations had severe LCA but normal physical and mental health."
The contrast case: patients with milder NMNAT1 alleles have no extra-retinal disease, which is what the threshold model has to explain.
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Discussions and Knowledge Gaps

1
Is nuclear NAD+ reduced in extra-retinal cells of SHILCA patients, and by more than in LCA9 patient cells?
KNOWLEDGE GAP OPEN gap_shilca_nad_measurement
Attached to
pathophysiology#Multi-Tissue Nuclear NAD+ Insufficiency
The multi-tissue NAD+ node and every edge from it to the skeletal, hearing and brain phenotypes rest on inference from NMNAT1 expression and mouse knockouts. Measuring NAD+ in SHILCA fibroblasts or blood alongside LCA9 and control samples would test the dosage model directly.
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Pathophysiology

3
NMNAT1 Severe Hypomorphic Loss of Function
An Alu-mediated tandem duplication spanning NMNAT1 exons 4 and 5 of the main isoform (c.299+526_*968dup) produces aberrant mRNAs and an approximately four-fold reduction in NMNAT1 expression in patient fibroblasts; some canonical transcript remains. In trans with the splice variant c.439+5G>T, total NMNAT1 mRNA in blood was about 25% lower than in controls and the isoform balance was disturbed. Because Nmnat1 knockout mice die as embryos and no human with biallelic null alleles is known, the duplication is interpreted as a strong but incomplete loss of function, more severe than the hypomorphs that cause retina-restricted LCA9.
NMNAT1 hgnc:17877 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NMNAT1 (hgnc:17877). hgnc:17877 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
nicotinamide-nucleotide adenylyltransferase activity GO:0000309 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased nicotinamide-nucleotide adenylyltransferase activity (GO:0000309). GO:0000309 is a molecular function from the Gene Ontology.
Downstream
Multi-Tissue Nuclear NAD+ Insufficiency NAD+ has not been measured in SHILCA patient cells. The link rests on NMNAT1 being the nuclear NAD+ synthase and on NAD+ falling when NMNAT1 is removed from human iPSC-derived retinal organoids.
Show evidence (5 references)
PMID:32533184 SUPPORT In vitro / ex vivo
"Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval."
RNA-seq of cultured patient fibroblasts shows strongly reduced NMNAT1 expression.
PMID:32533184 SUPPORT Human clinical
"Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs."
Identifies the causal structural variant and its transcript-level consequence.
PMID:32533184 SUPPORT INDIRECT Human clinical
"The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality."
The authors' dosage interpretation; enzymatic activity was not measured directly, so the severity ranking is inferred from expression and from the lethality of complete knockout.
+ 2 more references
Multi-Tissue Nuclear NAD+ Insufficiency
The working model for SHILCA is that the duplication lowers nuclear NAD+ synthesis below what skeletal, cochlear and central nervous system tissue tolerate, not only below the retina's threshold as in LCA9. Nmnat1 knockout mice die in utero, which shows that some NMNAT1 activity is required outside the retina. The tissue-specific steps between NAD+ shortfall and chondrodysplasia, hearing loss or hypomyelination have not been studied.
Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
nuclear NAD+ biosynthesis GO:0009435 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nuclear NAD+ biosynthesis, annotated with NAD+ biosynthetic process (GO:0009435). GO:0009435 is a biological process from the Gene Ontology.
Downstream
Photoreceptor Degeneration
Spondyloepiphyseal Dysplasia Hypothesized; no study links NAD+ shortfall to the growth plate. Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
Sensorineural Hearing Loss Hypothesized; the cochlear cell type and mechanism are unstudied. Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
CNS Hypomyelination Hypothesized; oligodendrocyte NAD+ has not been studied in this disorder. Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
Intellectual Disability Hypothesized; no neuronal mechanism has been studied. Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
Global Developmental Delay Hypothesized; no neuronal mechanism has been studied. Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
Brain Atrophy Hypothesized; reported in one patient only. Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
Cerebellar Atrophy Hypothesized; reported in one patient only. Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
Show evidence (1 reference)
PMID:32533184 SUPPORT INDIRECT BACKGROUND Model organism
"murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life"
Complete loss of NMNAT1 is not tolerated outside the retina in mouse, the basis for reading SHILCA as an extra-retinal NAD+ insufficiency. The paper restates prior mouse work rather than reporting it.
Photoreceptor Degeneration
The retinal component is the same process as in LCA9 (see Leber_Congenital_Amaurosis_9 for the PARP and SARM1 steps). Deleting Nmnat1 during retinal development in mouse causes early, severe photoreceptor loss through several cell death pathways. All SHILCA patients have congenital LCA; the compound heterozygous patient's electroretinogram was undetectable and her macular atrophy progressed.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
photoreceptor cell death GO:0008219 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased photoreceptor cell death, annotated with cell death (GO:0008219). GO:0008219 is a biological process from the Gene Ontology.
Downstream
Leber Congenital Amaurosis
Undetectable Electroretinogram
Macular Atrophy
Nystagmus
Optic Disc Pallor
Attenuation of Retinal Blood Vessels
Show evidence (2 references)
PMID:34878972 SUPPORT Model organism
"deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways"
Developmental loss of NMNAT1 produces early severe photoreceptor degeneration.
PMID:33107823 SUPPORT Model organism
"Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor."
NMNAT1 acts cell-autonomously in photoreceptors.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SHILCA Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Cardiovascular 1
Attenuation of Retinal Blood Vessels HP:0007843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Marked attenuation of retinal vessels, annotated with Attenuation of retinal blood vessels (HP:0007843). HP:0007843 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"the fundus examination showed mild optic disc pallor, marked attenuation of retinal vessels and widespread retinal pigmented epithelium alterations"
Fundus finding.
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32533184 SUPPORT Human clinical
"a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis"
Part of the defining tetrad in the index children.
PMID:33668384 SUPPORT Human clinical
"a severe ossification delay, spondylo-epiphyseal dysplasia and mild sensorineural hearing loss"
Mild in the compound heterozygous patient.
Eye 7
Leber Congenital Amaurosis Severely reduced visual acuity HP:0001141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leber congenital amaurosis, annotated with Severely reduced visual acuity (HP:0001141). HP:0001141 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32533184 SUPPORT Human clinical
"intellectual disability and Leber congenital amaurosis (SHILCA)"
Part of the defining tetrad.
PMID:33668384 SUPPORT Human clinical
"After almost two years of follow-up, the patient’s best corrected visual acuity (BCVA) was light perception"
Visual acuity reduced to light perception.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"the patient presented poor visual tracking with nystagmus and esotropia at the age of six months"
Nystagmus by six months.
Esotropia HP:0000565 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esotropia (HP:0000565). HP:0000565 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"the patient presented poor visual tracking with nystagmus and esotropia at the age of six months"
Esotropia by six months.
Undetectable Electroretinogram HP:0000550 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Extinguished scotopic and photopic electroretinogram, annotated with Undetectable electroretinogram (HP:0000550). HP:0000550 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"an electroretinogram (ERG) showed scotopic and photopic response below noise levels"
Rod and cone responses below noise.
Macular Atrophy HP:0007401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive geographic macular atrophy, annotated with Macular atrophy (HP:0007401), qualified as course progressive. HP:0007401 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:33668384 SUPPORT Human clinical
"In the macular region, areas of geographic atrophy mimicking the colobomatous lesions were found"
Pseudocolobomatous macular atrophy.
PMID:33668384 SUPPORT Human clinical
"the retinographies showed an evolution of the retinal involvement, with increased areas of geographic macular atrophy in both eyes"
The atrophy enlarged over two years.
Optic Disc Pallor HP:0000543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild optic disc pallor, annotated with Optic disc pallor (HP:0000543). HP:0000543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"the fundus examination showed mild optic disc pallor, marked attenuation of retinal vessels and widespread retinal pigmented epithelium alterations"
Fundus finding.
Hypermetropia HP:0000540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High hypermetropia, annotated with Hypermetropia (HP:0000540). HP:0000540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"The exploration under cyclorefraction showed a high hypermetropia of +8.00 diopters (Dp) in both eyes."
+8.00 D in both eyes.
Head and Neck 2
Coarse Facial Features HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild facial coarsening, annotated with Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"Moreover, facial appearance showed mild coarsening and a deep nasal bridge."
Facial gestalt in the fourth patient.
Depressed Nasal Bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep nasal bridge, annotated with Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"Moreover, facial appearance showed mild coarsening and a deep nasal bridge."
Facial gestalt in the fourth patient.
Musculoskeletal 5
Spondyloepiphyseal Dysplasia HP:0002655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe spondyloepiphyseal dysplasia, annotated with Spondyloepiphyseal dysplasia (HP:0002655). HP:0002655 is a phenotype from the Human Phenotype Ontology.
Sequelae: Severe Short Stature Delayed Skeletal Maturation
Show evidence (2 references)
PMID:32533184 SUPPORT Human clinical
"presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia"
Present in the three index children.
PMID:33668384 SUPPORT Human clinical
"These examinations revealed axial hypotonia with ataxia, a severe ossification delay, spondylo-epiphyseal dysplasia and mild sensorineural hearing loss."
Present in the fourth reported patient.
Delayed Skeletal Maturation HP:0002750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe ossification delay, annotated with Delayed skeletal maturation (HP:0002750). HP:0002750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"These examinations revealed axial hypotonia with ataxia, a severe ossification delay, spondylo-epiphyseal dysplasia and mild sensorineural hearing loss."
Severe ossification delay at two years.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT INDIRECT BACKGROUND Human clinical
"concrete symptoms, such as the intellectual disability or the biconcave spine profile and scoliosis, were not detected in our case"
Contrasts this patient with the previously reported SHILCA cases, which implies scoliosis in the Italian patients; the original report's full text was not available to quote.
Biconcave Vertebral Bodies HP:0004586 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Biconcave spine profile, annotated with Biconcave vertebral bodies (HP:0004586). HP:0004586 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT INDIRECT BACKGROUND Human clinical
"concrete symptoms, such as the intellectual disability or the biconcave spine profile and scoliosis, were not detected in our case"
Contrasts this patient with the previously reported SHILCA cases, which implies a biconcave spine profile in the Italian patients.
Axial Hypotonia HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"These examinations revealed axial hypotonia with ataxia"
Axial hypotonia at two years.
Nervous System 8
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32533184 SUPPORT Human clinical
"sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA)"
Part of the defining tetrad.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"including developmental delay with cervicoaxial hypotonia, short stature (skeletal dysplasia), generalized dyskinesia and erratic eye movements with absent fixation"
Developmental delay from five months.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"These examinations revealed axial hypotonia with ataxia"
Ataxia at two years.
Dyskinesia HP:0100660 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized dyskinesia, annotated with Dyskinesia (HP:0100660). HP:0100660 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"short stature (skeletal dysplasia), generalized dyskinesia and erratic eye movements with absent fixation"
Generalized dyskinesia in infancy.
CNS Hypomyelination HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomyelinating leukoencephalopathy, annotated with CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"The cranial MRI confirmed hypomyelinating leukoencephalopathy, although with few subcortical white matter myelinated islets, and progressive brain and cerebellum atrophy"
MRI finding at two years.
Brain Atrophy HP:0012444 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive brain atrophy, annotated with Brain atrophy (HP:0012444), qualified as course progressive. HP:0012444 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"The cranial MRI confirmed hypomyelinating leukoencephalopathy, although with few subcortical white matter myelinated islets, and progressive brain and cerebellum atrophy"
Progressive atrophy on serial MRI.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebellar atrophy, annotated with Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"progressive brain and cerebellum atrophy"
Cerebellar atrophy on serial MRI.
Hypoplasia of the Corpus Callosum HP:0002079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe corpus callosum hypoplasia, annotated with Hypoplasia of the corpus callosum (HP:0002079). HP:0002079 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"with mild ventricular expansion, subarachnoid space increase and severe corpus callosum hypoplasia"
Infant MRI finding.
Growth 1
Severe Short Stature HP:0003510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe short stature (HP:0003510). HP:0003510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33668384 SUPPORT Human clinical
"at which time the patient’s height was 72 cm (p < 1, −4.72 SD)"
Height -4.7 SD at two years.
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Genetic Associations

1
NMNAT1
Gene: NMNAT1 hgnc:17877 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NMNAT1 (hgnc:17877). hgnc:17877 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:33668384 SUPPORT Human clinical
"Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup."
Compound heterozygous genotype in the second family.
PMID:33668384 SUPPORT Human clinical
"This identical haplotype surrounding the rearrangement was also detected in an additional Spanish patient, indicative of a common and likely remote ancestral genetic event."
Shared haplotype indicates a founder duplication.
Variants (2)
NM_022787.3:c.299+526_*968dup Pathogenic
duplication
Alu-mediated tandem duplication of about 7.4 kb from intron 3 into the 3' UTR, covering exons 4 and 5 of the main isoform. Found on one shared haplotype in Italian and Spanish patients, consistent with an ancient founder event. Homozygous in the three index children.
NM_022787.3:c.439+5G>T Pathogenic
splice region
Exon 4 donor splice-site variant; increases an intron 4 retention transcript. Reported in trans with the duplication in one patient.
🔬

Diagnosis

1
Genome Sequencing for NMNAT1 Structural Variant
The duplication was missed by exome sequencing in the index families and was found only after RNA sequencing showed low NMNAT1 expression, followed by short- and long-read genome sequencing. In the second family it was suspected from exome read depth and confirmed by genome sequencing.
Show evidence (2 references)
PMID:32533184 SUPPORT Human clinical
"Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere."
Exome sequencing alone missed the causal variant.
PMID:33668384 SUPPORT Human clinical
"An increase in reads involving two of the five exons of NMNAT1 (exons 4 and 5, NM_022787.3) could be detected, consistent with a heterozygous duplication of this region."
In the second family the duplication was suspected from exome read depth.
{ }

Source YAML

click to show 
name: SHILCA Syndrome
creation_date: "2026-10-21T00:00:00Z"
category: Mendelian
parents:
- NMNAT1-related retinopathy
- Leber congenital amaurosis
- Spondyloepiphyseal dysplasia
synonyms:
- SHILCA
- spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and Leber congenital amaurosis
- spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis
description: >-
  SHILCA syndrome is an autosomal recessive multisystem disorder caused by
  biallelic NMNAT1 alleles that reduce expression of the nuclear NAD+ synthase
  more severely than the alleles behind retina-restricted Leber congenital
  amaurosis 9. The defining features are a severe spondyloepiphyseal
  dysplasia, sensorineural hearing loss, intellectual disability and Leber
  congenital amaurosis, with brain anomalies on MRI. The one compound
  heterozygous patient described in detail also had severe short stature,
  hypomyelinating leukoencephalopathy, progressive brain and cerebellar
  atrophy, corpus callosum hypoplasia and pseudocolobomatous macular atrophy.
  Every reported patient carries an Alu-mediated duplication of NMNAT1 exons
  4-5 on a shared founder haplotype, either homozygous or in trans with a
  splice variant. The duplication cuts NMNAT1 expression roughly four-fold and
  produces aberrant transcripts. Complete loss of Nmnat1 is embryonic lethal
  in mice, so the authors read SHILCA as the intermediate point on an NMNAT1
  dosage series between LCA9 and lethality. That extra-retinal tissues fail
  because nuclear NAD+ falls below what they tolerate is a hypothesis; NAD+
  has not been measured in patients. Four patients are published.
disease_term:
  preferred_term: SHILCA syndrome
  term:
    id: MONDO:0031007
    label: spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous NMNAT1 exon 4-5 duplication in three Italian children from two
    families, and compound heterozygosity for the same duplication with a
    paternally inherited splice variant in one Spanish child.
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with a previously unrecognized autosomal recessive disorder"
    explanation: The index report describes the disorder as autosomal recessive.
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype."
    explanation: The affected children share an autozygous NMNAT1-containing interval, consistent with recessive inheritance.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, the splicing mutation and the duplication detected in the patient were present in heteroallelic combination, in accordance with the proposed inheritance pattern and the familial history"
    explanation: Compound heterozygosity with parental segregation in a second family.
pathophysiology:
- name: NMNAT1 Severe Hypomorphic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    An Alu-mediated tandem duplication spanning NMNAT1 exons 4 and 5 of the
    main isoform (c.299+526_*968dup) produces aberrant mRNAs and an
    approximately four-fold reduction in NMNAT1 expression in patient
    fibroblasts; some canonical transcript remains. In trans with the splice
    variant c.439+5G>T, total NMNAT1 mRNA in blood was about 25% lower than in
    controls and the isoform balance was disturbed. Because Nmnat1 knockout
    mice die as embryos and no human with biallelic null alleles is known, the
    duplication is interpreted as a strong but incomplete loss of function,
    more severe than the hypomorphs that cause retina-restricted LCA9.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  genes:
  - preferred_term: NMNAT1
    term:
      id: hgnc:17877
      label: NMNAT1
  molecular_functions:
  - preferred_term: nicotinamide-nucleotide adenylyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0000309
      label: nicotinamide-nucleotide adenylyltransferase activity
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval."
    explanation: RNA-seq of cultured patient fibroblasts shows strongly reduced NMNAT1 expression.
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs."
    explanation: Identifies the causal structural variant and its transcript-level consequence.
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality."
    explanation: >-
      The authors' dosage interpretation; enzymatic activity was not measured
      directly, so the severity ranking is inferred from expression and from
      the lethality of complete knockout.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The total NMNAT1 expression in the patient was decreased by approximately 25% compared with that of the control subjects."
    explanation: Reduced NMNAT1 expression in the compound heterozygous patient's blood.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These alterations are most probably responsible for the multisystem involvement instead of a retina-restricted degeneration, as they compromise the correct NMNAT1 expression by unbalancing the relative levels of all isoforms and reducing the expression of the canonical variant."
    explanation: The authors attribute the multisystem rather than retina-restricted phenotype to the depth of the expression defect.
  downstream:
  - target: Multi-Tissue Nuclear NAD+ Insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      NAD+ has not been measured in SHILCA patient cells. The link rests on
      NMNAT1 being the nuclear NAD+ synthase and on NAD+ falling when NMNAT1
      is removed from human iPSC-derived retinal organoids.
    evidence:
    - reference: PMID:39446354
      reference_title: NMNAT1 Is Essential for Human iPS Cell Differentiation to the Retinal Lineage.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Decreased intracellular NAD levels and poly(ADP-ribosyl)ation were observed in NMNAT1-KO organoids at 7 to 10 days of the culture."
      explanation: NMNAT1 knockout lowers NAD in human cells; SHILCA alleles are partial, not null, so this is an inference.
- name: Multi-Tissue Nuclear NAD+ Insufficiency
  biological_scale: MOLECULAR
  description: >-
    The working model for SHILCA is that the duplication lowers nuclear NAD+
    synthesis below what skeletal, cochlear and central nervous system tissue
    tolerate, not only below the retina's threshold as in LCA9. Nmnat1
    knockout mice die in utero, which shows that some NMNAT1 activity is
    required outside the retina. The tissue-specific steps between NAD+
    shortfall and chondrodysplasia, hearing loss or hypomyelination have not
    been studied.
  biological_processes:
  - preferred_term: nuclear NAD+ biosynthesis
    modifier: DECREASED
    term:
      id: GO:0009435
      label: NAD+ biosynthetic process
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life"
    explanation: >-
      Complete loss of NMNAT1 is not tolerated outside the retina in mouse,
      the basis for reading SHILCA as an extra-retinal NAD+ insufficiency.
      The paper restates prior mouse work rather than reporting it.
  downstream:
  - target: Photoreceptor Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33107823
      reference_title: SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss."
      explanation: Shown with adult conditional Nmnat1 deletion in mouse; applied to SHILCA by inference.
  - target: Spondyloepiphyseal Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesized; no study links NAD+ shortfall to the growth plate.
    hypothesis_groups:
    - nmnat1_extraretinal_nad_threshold
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesized; the cochlear cell type and mechanism are unstudied.
    hypothesis_groups:
    - nmnat1_extraretinal_nad_threshold
  - target: CNS Hypomyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesized; oligodendrocyte NAD+ has not been studied in this disorder.
    hypothesis_groups:
    - nmnat1_extraretinal_nad_threshold
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesized; no neuronal mechanism has been studied.
    hypothesis_groups:
    - nmnat1_extraretinal_nad_threshold
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesized; no neuronal mechanism has been studied.
    hypothesis_groups:
    - nmnat1_extraretinal_nad_threshold
  - target: Brain Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesized; reported in one patient only.
    hypothesis_groups:
    - nmnat1_extraretinal_nad_threshold
  - target: Cerebellar Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypothesized; reported in one patient only.
    hypothesis_groups:
    - nmnat1_extraretinal_nad_threshold
- name: Photoreceptor Degeneration
  biological_scale: CELLULAR
  description: >-
    The retinal component is the same process as in LCA9 (see
    Leber_Congenital_Amaurosis_9 for the PARP and SARM1 steps). Deleting
    Nmnat1 during retinal development in mouse causes early, severe
    photoreceptor loss through several cell death pathways. All SHILCA
    patients have congenital LCA; the compound heterozygous patient's
    electroretinogram was undetectable and her macular atrophy progressed.
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: photoreceptor cell death
    modifier: INCREASED
    term:
      id: GO:0008219
      label: cell death
  evidence:
  - reference: PMID:34878972
    reference_title: Nuclear NAD(+)-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways"
    explanation: Developmental loss of NMNAT1 produces early severe photoreceptor degeneration.
  - reference: PMID:33107823
    reference_title: SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor."
    explanation: NMNAT1 acts cell-autonomously in photoreceptors.
  downstream:
  - target: Leber Congenital Amaurosis
  - target: Undetectable Electroretinogram
  - target: Macular Atrophy
  - target: Nystagmus
  - target: Optic Disc Pallor
  - target: Attenuation of Retinal Blood Vessels
phenotypes:
- name: Spondyloepiphyseal Dysplasia
  category: Skeletal
  description: Severe spondyloepiphyseal dysplasia with marked delay of ossification.
  sequelae:
  - target: Severe Short Stature
    causal_link_type: DIRECT
  - target: Delayed Skeletal Maturation
    causal_link_type: DIRECT
  phenotype_term:
    preferred_term: Severe spondyloepiphyseal dysplasia
    term:
      id: HP:0002655
      label: Spondyloepiphyseal dysplasia
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia"
    explanation: Present in the three index children.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These examinations revealed axial hypotonia with ataxia, a severe ossification delay, spondylo-epiphyseal dysplasia and mild sensorineural hearing loss."
    explanation: Present in the fourth reported patient.
- name: Delayed Skeletal Maturation
  category: Skeletal
  phenotype_term:
    preferred_term: Severe ossification delay
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These examinations revealed axial hypotonia with ataxia, a severe ossification delay, spondylo-epiphyseal dysplasia and mild sensorineural hearing loss."
    explanation: Severe ossification delay at two years.
- name: Scoliosis
  category: Skeletal
  description: Reported in the Italian index patients; absent in the compound heterozygous patient.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "concrete symptoms, such as the intellectual disability or the biconcave spine profile and scoliosis, were not detected in our case"
    explanation: >-
      Contrasts this patient with the previously reported SHILCA cases, which
      implies scoliosis in the Italian patients; the original report's full
      text was not available to quote.
- name: Biconcave Vertebral Bodies
  category: Skeletal
  description: Biconcave spine profile reported in the Italian index patients; absent in the compound heterozygous patient.
  phenotype_term:
    preferred_term: Biconcave spine profile
    term:
      id: HP:0004586
      label: Biconcave vertebral bodies
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "concrete symptoms, such as the intellectual disability or the biconcave spine profile and scoliosis, were not detected in our case"
    explanation: >-
      Contrasts this patient with the previously reported SHILCA cases, which
      implies a biconcave spine profile in the Italian patients.
- name: Severe Short Stature
  category: Growth
  phenotype_term:
    preferred_term: Severe short stature
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at which time the patient’s height was 72 cm (p < 1, −4.72 SD)"
    explanation: Height -4.7 SD at two years.
- name: Sensorineural Hearing Loss
  category: Audiological
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis"
    explanation: Part of the defining tetrad in the index children.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a severe ossification delay, spondylo-epiphyseal dysplasia and mild sensorineural hearing loss"
    explanation: Mild in the compound heterozygous patient.
- name: Intellectual Disability
  category: Neurological
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA)"
    explanation: Part of the defining tetrad.
- name: Global Developmental Delay
  category: Neurological
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including developmental delay with cervicoaxial hypotonia, short stature (skeletal dysplasia), generalized dyskinesia and erratic eye movements with absent fixation"
    explanation: Developmental delay from five months.
- name: Axial Hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These examinations revealed axial hypotonia with ataxia"
    explanation: Axial hypotonia at two years.
- name: Ataxia
  category: Neurological
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These examinations revealed axial hypotonia with ataxia"
    explanation: Ataxia at two years.
- name: Dyskinesia
  category: Neurological
  phenotype_term:
    preferred_term: Generalized dyskinesia
    term:
      id: HP:0100660
      label: Dyskinesia
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature (skeletal dysplasia), generalized dyskinesia and erratic eye movements with absent fixation"
    explanation: Generalized dyskinesia in infancy.
- name: CNS Hypomyelination
  category: Neurological
  description: Hypomyelinating leukoencephalopathy with only a few myelinated subcortical white matter islets.
  phenotype_term:
    preferred_term: Hypomyelinating leukoencephalopathy
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cranial MRI confirmed hypomyelinating leukoencephalopathy, although with few subcortical white matter myelinated islets, and progressive brain and cerebellum atrophy"
    explanation: MRI finding at two years.
- name: Brain Atrophy
  category: Neurological
  phenotype_term:
    preferred_term: Progressive brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cranial MRI confirmed hypomyelinating leukoencephalopathy, although with few subcortical white matter myelinated islets, and progressive brain and cerebellum atrophy"
    explanation: Progressive atrophy on serial MRI.
- name: Cerebellar Atrophy
  category: Neurological
  phenotype_term:
    preferred_term: Progressive cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive brain and cerebellum atrophy"
    explanation: Cerebellar atrophy on serial MRI.
- name: Hypoplasia of the Corpus Callosum
  category: Neurological
  phenotype_term:
    preferred_term: Severe corpus callosum hypoplasia
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with mild ventricular expansion, subarachnoid space increase and severe corpus callosum hypoplasia"
    explanation: Infant MRI finding.
- name: Leber Congenital Amaurosis
  category: Ophthalmological
  description: >-
    Congenital retinal dystrophy with poor visual tracking from early infancy;
    vision reduced to light perception by two years.
  phenotype_term:
    preferred_term: Leber congenital amaurosis
    term:
      id: HP:0001141
      label: Severely reduced visual acuity
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intellectual disability and Leber congenital amaurosis (SHILCA)"
    explanation: Part of the defining tetrad.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After almost two years of follow-up, the patient’s best corrected visual acuity (BCVA) was light perception"
    explanation: Visual acuity reduced to light perception.
- name: Nystagmus
  category: Ophthalmological
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient presented poor visual tracking with nystagmus and esotropia at the age of six months"
    explanation: Nystagmus by six months.
- name: Esotropia
  category: Ophthalmological
  phenotype_term:
    preferred_term: Esotropia
    term:
      id: HP:0000565
      label: Esotropia
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient presented poor visual tracking with nystagmus and esotropia at the age of six months"
    explanation: Esotropia by six months.
- name: Undetectable Electroretinogram
  category: Ophthalmological
  phenotype_term:
    preferred_term: Extinguished scotopic and photopic electroretinogram
    term:
      id: HP:0000550
      label: Undetectable electroretinogram
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an electroretinogram (ERG) showed scotopic and photopic response below noise levels"
    explanation: Rod and cone responses below noise.
- name: Macular Atrophy
  category: Ophthalmological
  description: >-
    Geographic macular atrophy mimicking coloboma, enlarging over follow-up, as
    in the macular pseudocoloboma typical of NMNAT1 retinopathy.
  phenotype_term:
    preferred_term: Progressive geographic macular atrophy
    term:
      id: HP:0007401
      label: Macular atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the macular region, areas of geographic atrophy mimicking the colobomatous lesions were found"
    explanation: Pseudocolobomatous macular atrophy.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the retinographies showed an evolution of the retinal involvement, with increased areas of geographic macular atrophy in both eyes"
    explanation: The atrophy enlarged over two years.
- name: Optic Disc Pallor
  category: Ophthalmological
  phenotype_term:
    preferred_term: Mild optic disc pallor
    term:
      id: HP:0000543
      label: Optic disc pallor
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the fundus examination showed mild optic disc pallor, marked attenuation of retinal vessels and widespread retinal pigmented epithelium alterations"
    explanation: Fundus finding.
- name: Attenuation of Retinal Blood Vessels
  category: Ophthalmological
  phenotype_term:
    preferred_term: Marked attenuation of retinal vessels
    term:
      id: HP:0007843
      label: Attenuation of retinal blood vessels
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the fundus examination showed mild optic disc pallor, marked attenuation of retinal vessels and widespread retinal pigmented epithelium alterations"
    explanation: Fundus finding.
- name: Hypermetropia
  category: Ophthalmological
  phenotype_term:
    preferred_term: High hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The exploration under cyclorefraction showed a high hypermetropia of +8.00 diopters (Dp) in both eyes."
    explanation: +8.00 D in both eyes.
- name: Coarse Facial Features
  category: Craniofacial
  phenotype_term:
    preferred_term: Mild facial coarsening
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, facial appearance showed mild coarsening and a deep nasal bridge."
    explanation: Facial gestalt in the fourth patient.
- name: Depressed Nasal Bridge
  category: Craniofacial
  phenotype_term:
    preferred_term: Deep nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, facial appearance showed mild coarsening and a deep nasal bridge."
    explanation: Facial gestalt in the fourth patient.
genetic:
- name: NMNAT1
  gene_term:
    preferred_term: NMNAT1
    term:
      id: hgnc:17877
      label: NMNAT1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  variants:
  - name: NM_022787.3:c.299+526_*968dup
    type: duplication
    clinical_significance: PATHOGENIC
    description: >-
      Alu-mediated tandem duplication of about 7.4 kb from intron 3 into the
      3' UTR, covering exons 4 and 5 of the main isoform. Found on one shared
      haplotype in Italian and Spanish patients, consistent with an ancient
      founder event. Homozygous in the three index children.
  - name: NM_022787.3:c.439+5G>T
    type: splice region
    clinical_significance: PATHOGENIC
    description: >-
      Exon 4 donor splice-site variant; increases an intron 4 retention
      transcript. Reported in trans with the duplication in one patient.
  notes: >-
    No patient with biallelic NMNAT1 null alleles is known. NMNAT1 missense and
    splice alleles cause retina-restricted LCA9, curated separately as
    Leber_Congenital_Amaurosis_9.
  evidence:
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup."
    explanation: Compound heterozygous genotype in the second family.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This identical haplotype surrounding the rearrangement was also detected in an additional Spanish patient, indicative of a common and likely remote ancestral genetic event."
    explanation: Shared haplotype indicates a founder duplication.
diagnosis:
- name: Genome Sequencing for NMNAT1 Structural Variant
  description: >-
    The duplication was missed by exome sequencing in the index families and
    was found only after RNA sequencing showed low NMNAT1 expression, followed
    by short- and long-read genome sequencing. In the second family it was
    suspected from exome read depth and confirmed by genome sequencing.
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere."
    explanation: Exome sequencing alone missed the causal variant.
  - reference: PMID:33668384
    reference_title: "New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An increase in reads involving two of the five exons of NMNAT1 (exons 4 and 5, NM_022787.3) could be detected, consistent with a heterozygous duplication of this region."
    explanation: In the second family the duplication was suspected from exome read depth.
mechanistic_hypotheses:
- hypothesis_group_id: nmnat1_extraretinal_nad_threshold
  hypothesis_label: Extra-retinal tissues fail below an NMNAT1/NAD+ dosage threshold
  status: EMERGING
  description: >-
    The SHILCA alleles leave less NMNAT1 than LCA9 alleles do, and complete
    loss is embryonic lethal in mice. The proposal is that skeletal, cochlear
    and brain tissue tolerate the LCA9 reduction but not the SHILCA one.
    Neither NAD+ levels nor any tissue-specific step has been measured in
    patients or in a model carrying SHILCA alleles.
  evidence:
  - reference: PMID:32533184
    reference_title: "An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality."
    explanation: The authors' own dosage proposal.
  - reference: PMID:22842230
    reference_title: Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals with biallelic NMNAT1 mutations had severe LCA but normal physical and mental health."
    explanation: >-
      The contrast case: patients with milder NMNAT1 alleles have no
      extra-retinal disease, which is what the threshold model has to explain.
discussions:
- discussion_id: gap_shilca_nad_measurement
  prompt: >-
    Is nuclear NAD+ reduced in extra-retinal cells of SHILCA patients, and by
    more than in LCA9 patient cells?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Multi-Tissue Nuclear NAD+ Insufficiency
  rationale: >-
    The multi-tissue NAD+ node and every edge from it to the skeletal,
    hearing and brain phenotypes rest on inference from NMNAT1 expression and
    mouse knockouts. Measuring NAD+ in SHILCA fibroblasts or blood alongside
    LCA9 and control samples would test the dosage model directly.
notes: >-
  Four patients from three families have been published (two Italian
  families with three homozygous children, one Spanish child compound
  heterozygous). Many features here (short stature, ossification delay,
  hypotonia, ataxia, dyskinesia, the detailed MRI and fundus findings,
  hypermetropia and facial features) are documented only for the Spanish
  child, because the index report is available only as an abstract. That
  child had milder hearing loss and, at two years, no detectable
  intellectual disability, biconcave spine or scoliosis. No GeneReviews
  chapter covers SHILCA. A homozygous NMNAT1
  p.Glu257Lys family with pure hereditary spastic paraplegia and no retinal
  disease (PMID:36871412) is a separate, unconfirmed NMNAT1 phenotype and is
  not included here. No treatment has been studied; care is supportive.
📚

References & Deep Research

Deep Research

1

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 (1)

Create: SHILCA_Syndrome · 2026-10-21T03:59:27Z · View source

New entry for SHILCA syndrome (MONDO:0031007), the syndromic NMNAT1 disorder that Leber_Congenital_Amaurosis_9 explicitly excludes. Curated as a separate Disease because its multisystem phenotype reflects a deeper NMNAT1 dosage loss than LCA9. Phenotypes, inheritance and variants come from the only two SHILCA reports: Bedoni 2020 (PMID:32533184, abstract only) and Abad-Morales 2021 (PMID:33668384, PMC full text). Mechanism nodes use NMNAT1 mouse and human iPSC evidence (PMID:34878972, 33107823, 39446354, 22842230), marked INDIRECT where applied to SHILCA by inference; NAD+ has not been measured in SHILCA patients. Deep research was requested from falcon, which is not configured here; the run used --fallback and openscientist produced research/SHILCA_Syndrome-deep-research-openscientist.md (18/18 references resolved; one unsupported quote, PMID:41922335, not cited here). just preflight-dr returned SKIP because MONDO records no causal gene for the term; manual check found the report is about NMNAT1/SHILCA (OMIM 619260; the report's OMIM 608553 is the NMNAT1 gene record). The report's Orphanet-derived features (ORPHA:611207, e.g. platyspondyly, dental findings) were not added because Orphadata could not be downloaded through the network proxy, so the record could not be cached and quoted. The report's NMNAT1-LCA natural-history paper (PMID:39710161) was not used because it concerns LCA9, not SHILCA. No GeneReviews chapter exists (just check-genereviews: NO_CHAPTER). Validated with just validate, validate-terms, count-verified-snippets (44/44), check-entity-refs, check-causal-targets and validate-disorders. A fresh-context self-review before the PR led to: the extra-retinal NAD+ edges grouped under an EMERGING mechanistic hypothesis with a KNOWLEDGE_GAP discussion (NAD+ unmeasured in patients); fibroblast RNA-seq regraded IN_VITRO; GO:0006915 replaced by GO:0008219 cell death, since NMNAT1 loss kills photoreceptors by several pathways; single-patient features marked as such in description and notes; scoliosis and biconcave vertebral bodies added from the second report's comparison with the index cases; additional retinal and skeletal edges wired.

OpenScientist ▸
SHILCA Syndrome: A Comprehensive Disease Characteristics Report
openscientist-autonomous 17 citations 2026-10-21T03:56:54.133726

SHILCA Syndrome: A Comprehensive Disease Characteristics Report

Disease: SHILCA Syndrome (Spondylo-epiphyseal dysplasia, sensorineural Hearing loss, Impaired Intellectual development, and Leber Congenital Amaurosis) MONDO ID: MONDO:0031007 · OMIM: 619260 · Orphanet: 611207 · Category: Mendelian (autosomal recessive) Causal gene: NMNAT1 (1p36.22; HGNC:17877; NCBI Gene 64802)

Summary

SHILCA syndrome is an ultra-rare autosomal recessive multisystem disorder first delineated in 2020, defined by the tetrad of Spondylo-epiphyseal dysplasia, sensorineural Hearing loss, Impaired intellectual development (with brain MRI anomalies), and Leber Congenital Amaurosis (SHILCA). It is caused by biallelic hypomorphic (dosage-reducing) variants in NMNAT1, the gene encoding the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, the enzyme that catalyzes the terminal step of NAD⁺ biosynthesis. The archetypal mutation is an Alu-mediated intragenic partial duplication (c.299+526_968dup) that reduces, but does not abolish, NMNAT1 expression — a critical point, because complete loss of NMNAT1 is embryonic-lethal in mice. The disorder is extraordinarily rare: only approximately four patients from three families* have been reported worldwide (PMID: 32533184, PMID: 33668384).

Mechanistically, reduced NMNAT1 function lowers nuclear NAD⁺, which compromises PARP1-dependent DNA repair and sirtuin (SIRT1)-dependent stress adaptation and redox buffering. In the best-studied tissue — the retina — this converges on the progressive accumulation of the oxidative DNA adduct 8-oxo-dG, triggering apoptotic photoreceptor loss. The same NAD⁺-dependent vulnerability is inferred to extend to other metabolically demanding, long-lived cells: central neurons and oligodendrocytes (explaining intellectual disability, hypomyelinating leukoencephalopathy, and cerebellar hypoplasia), cochlear hair cells (sensorineural deafness), and chondrocytes (skeletal dysplasia). NMNAT1 sits at the center of a broad allelic series that ranges from isolated non-syndromic Leber congenital amaurosis (LCA9) and cone/cone-rod dystrophy at the mild end, through hereditary spastic paraplegia, to the severe syndromic SHILCA phenotype.

There is no approved disease-modifying therapy; management is entirely supportive and multidisciplinary (low-vision/blindness rehabilitation, cochlear implants, developmental/physical/occupational/speech therapy, orthopedic and dental care), coupled with autosomal-recessive genetic counseling (25% sibling recurrence risk). However, AAV-mediated NMNAT1 gene augmentation preserves retinal structure and function in mouse models, and the oxidative-DNA-damage mechanism, NAD⁺-precursor supplementation, and SARM1 inhibition define rational, actively developing therapeutic avenues. A key diagnostic lesson is that SHILCA is a "WES-negative" structural/splice disorder that evades standard whole-exome sequencing and requires RNA-seq plus (ideally long-read) whole-genome sequencing to solve.

1. Disease Information

Overview. SHILCA is a Mendelian, autosomal recessive, congenital multisystem syndrome combining a severe inherited retinal dystrophy (Leber congenital amaurosis) with sensorineural hearing loss, intellectual disability/brain anomalies, and a severe skeletal (spondylo-epiphyseal) dysplasia. It was first described by Bedoni et al. in 2020 in three children from two unrelated Italian families "presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA)" (PMID: 32533184).

Key identifiers (Finding F010).

Resource Identifier
MONDO MONDO:0031007
OMIM (disease) 619260 (distinct from LCA9, OMIM 608553)
OMIM (gene NMNAT1) 608700
Orphanet ORPHA:611207
DOID DOID:0112290
GARD 0018025
MedGen C1780157
UMLS C5543257
ICD-10 / ICD-11 No dedicated code (maps to generic hereditary retinal dystrophy H35.5 / 9B76)
MeSH None (ultra-rare)

Synonyms: "SHILCA syndrome"; "SHILCA"; full name "Spondyloepiphyseal dysplasia, sensorineural Hearing loss, Impaired intellectual development, and Leber Congenital Amaurosis."

Source of information. Knowledge of SHILCA is derived entirely from individual patient case reports and functional/model studies — aggregated disease-level resources are minimal, reflecting its ultra-rare Mendelian nature (F010).

2. Etiology

Primary cause (genetic). SHILCA is a monogenic disorder caused by biallelic (recessive) hypomorphic variants in NMNAT1. There is no environmental, infectious, or multifactorial contribution. The original families carried an Alu-mediated partial duplication of NMNAT1: "Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs" (PMID: 32533184) (F001).

Genetic risk factors. The disease-defining variants are the NMNAT1 alleles themselves. The second reported patient was compound heterozygous for a novel splice variant and the recurrent duplication: "two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1)... c.439+5G>T and c.299+526_968dup" (PMID: 33668384) (F006). Because the phenotype requires residual NMNAT1 activity* (complete loss is lethal), the specific combination of hypomorphic alleles is itself the determinant of whether the syndromic (versus isolated ocular) phenotype emerges.

Environmental risk / protective factors. None established for the human disease. In mouse models, light exposure exacerbates photoreceptor degeneration in sensitized genotypes (compound heterozygous Nmnat1^E257K/−), suggesting phototoxic/oxidative stress can act as a gene–environment modifier of the ocular component (PMID: 29674119) (F007). No protective alleles or dietary/lifestyle protective factors are documented. Conceptually, NAD⁺-precursor availability is a candidate modifiable factor given the biochemical defect, but this is unproven in SHILCA.

Gene–environment interactions. The clearest example is the light-dependent exacerbation of retinal degeneration in hypomorphic Nmnat1 mice (F007). The underlying oxidative DNA-damage mechanism (8-oxo-dG accumulation) implies that oxidative load — metabolic and photic — modulates tissue vulnerability (F003).

3. Phenotypes

SHILCA is a severe, congenital, multisystem phenotype. Orphanet classifies it as "a rare primary bone dysplasia" and expands the core tetrad with prominent CNS, neuromuscular, craniofacial, and dental features (F012).

Phenotype Type HPO term Onset / course Frequency
Leber congenital amaurosis Clinical sign (ophthalmic) HP:0030512 Congenital; rapid progression → stabilizes ~age 4 Universal (cardinal)
Retinal degeneration Clinical sign HP:0000546 Congenital, progressive Universal
Macular/central retinal atrophy Clinical sign HP:0007401 Coalesces into central scar by age 2 Universal
Optic atrophy Clinical sign HP:0000648 Early, progressive Common
Nystagmus Clinical sign HP:0000639 Infantile Common
Hyperopia Lab/refractive HP:0000540 Congenital Universal in NMNAT1-LCA
Sensorineural hearing impairment Clinical sign HP:0000407 Congenital/early Cardinal
Intellectual disability Behavioral/cognitive HP:0001249 Developmental Cardinal
Global developmental delay Behavioral/cognitive HP:0001263 Infantile Common
Spondylo-epiphyseal dysplasia / platyspondyly Physical/skeletal HP:0002655 Congenital Cardinal
Delayed CNS myelination Imaging/neurologic HP:0002188 Infantile Reported
Leukoencephalopathy (hypomyelinating) Imaging/neurologic HP:0002352 Infantile Reported
Cerebral hypoplasia Imaging HP:0006872 Congenital Reported
Cerebellar atrophy/hypoplasia Imaging HP:0001272 Infantile Reported
Generalized hypotonia Clinical sign HP:0001252 Early Reported
Ataxia Clinical sign HP:0001251 Childhood Reported
Depressed nasal bridge Dysmorphic HP:0005280 Congenital Reported
Wide mouth Dysmorphic HP:0000154 Congenital Reported
Abnormal dentition Dental HP:0000164 Childhood Reported

Ocular natural history (F008). The retinal phenotype follows a stereotyped course: "All patients exhibited early-onset, rapidly progressive bilateral retinal degeneration with pronounced central involvement. The condition was characterized by multiple atrophic lesions that coalesced into a large central retinal scar by age 2. The condition stabilized around 4 years of age" (PMID: 39710161). Patients are hyperopic with undetectable ERG and VEP responses; most retain light-perception vision or better with minimal acuity deterioration after age 2.

Quality of life impact. The combination produces deaf-blindness plus intellectual disability and skeletal/motor disability — among the most severe possible multi-domain impairments — with lifelong dependence and need for specialized education and rehabilitation (F015). No disease-specific EQ-5D/SF-36/PROMIS data exist given the tiny patient count.

4. Genetic / Molecular Information

Causal gene. NMNAT1 (nicotinamide mononucleotide adenylyltransferase 1), chromosome 1p36.22, ENSG00000173614, HGNC:17877, OMIM gene 608700, transcript NM_022787. It encodes the nuclear NAD⁺-synthesizing enzyme (F002, F009, F011).

Pathogenic variants in SHILCA. - c.299+526_*968dup — recurrent Alu-mediated intragenic partial duplication (2 of 5 exons), producing aberrant mRNAs; reduces expression ~4-fold (hypomorphic, not null) (PMID: 32533184). - c.439+5G>T — novel non-canonical splice variant producing aberrant transcripts (second patient, compound heterozygous with the duplication) (PMID: 33668384).

All variants are germline, autosomal recessive, with a loss/reduction-of-function (hypomorphic) consequence — not gain of function (F009).

Broader NMNAT1 allelic series (F004). NMNAT1 exhibits a remarkable genotype–phenotype spectrum, with most pathogenic variants clustering in exon 5:

Variant cDNA Phenotype Reference
p.Glu257Lys c.769G>A Most common LCA9 hypomorph; incompletely penetrant PMID: 24830548
p.Val9Met c.25G>A Classic LCA9 (homozygous siblings) PMID: 22842229
p.Asn18Ser c.53A>G Milder, later-onset retinal dystrophy (with E257K) PMID: 30004997
p.Glu91Lys / E257K+N18S — Cone / cone-rod dystrophy with macular atrophy PMID: 29184169
p.E257K (homozygous) c.769G>A Hereditary spastic paraplegia PMID: 36871412
Duplication + splice c.299+526_*968dup; c.439+5G>T Syndromic SHILCA PMID: 32533184, PMID: 33668384

The most common allele, p.Glu257Lys, "was observed in 38 of 106 alleles (35.8%)" and "is considered not fully penetrant" — it "was 80-fold less frequent in a homozygous state in patients... than predicted based on its heterozygosity frequency" (PMID: 24830548) (F004, F009).

Population allele frequencies (gnomAD v4; F009).

Variant rsID Allele frequency Notes
p.Glu257Lys rs150726175 ~1.03×10⁻³ (~0.1%; carrier ~1/485) Common but reduced-penetrance hypomorph
p.Val9Met rs387907294 ~3.4×10⁻⁶ Ultra-rare, deleterious
p.Asn18Ser rs748902766 ~3.7×10⁻⁵ Rare
SHILCA duplication / splice — Not in gnomAD (private) Explains extreme rarity

This frequency structure — a common weak hypomorph alongside ultra-rare genuinely deleterious alleles — explains why isolated LCA9 is the predominant presentation while syndromic SHILCA is vanishingly rare (F009).

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes are established for SHILCA, though p.E257K has been proposed to act as a modifier allele in other LCA genetic subtypes (PMID: 24940029, supportive). No disease-specific DNA-methylation or histone-modification signature is defined. No large-scale chromosomal abnormality is involved — the lesion is a small intragenic structural (duplication) variant detectable only by WGS (F014).

5. Environmental Information

SHILCA is a purely genetic disorder; no environmental, lifestyle, or infectious etiology applies. The only environmental modifier with experimental support is light exposure, which exacerbates retinal degeneration in sensitized hypomorphic Nmnat1 mouse models (F007, PMID: 29674119). No toxin, radiation, occupational exposure, dietary factor, or infectious agent is implicated.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic hypomorphic NMNAT1 variants (Alu-mediated partial duplication ± splice variant) → reduced NMNAT1 mRNA/protein (~4-fold downregulation in patient fibroblasts) — demonstrated (PMID: 32533184).
  2. Reduced NMNAT1 enzyme → decreased nuclear NAD⁺ biosynthesis (NMNAT1 catalyzes the terminal step, NMN + ATP → NAD⁺) — demonstrated biochemically (F011, F013).
  3. Lower nuclear NAD⁺ → impaired PARP1-dependent DNA repair and reduced SIRT1-dependent stress/redox adaptation — inferred from NMNAT1–PARP1 interaction and NAD⁺ biology (F011, F013).
  4. Impaired repair + redox buffering → accumulation of oxidative DNA damage (8-oxo-dG) in vulnerable post-mitotic cells — demonstrated in photoreceptors (PMID: 41922335) (F003).
  5. Oxidative DNA damage → apoptotic cell loss — demonstrated in photoreceptors; inferred for other tissues (F003).
  6. Branch point — tissue-specific manifestations (driven by high metabolic/NAD⁺ demand and cell longevity):
  7. → Photoreceptors degenerate → Leber congenital amaurosis (demonstrated).
  8. → Central neurons / oligodendrocytes → intellectual disability, hypomyelinating leukoencephalopathy, cerebellar hypoplasia (inferred).
  9. → Cochlear hair cells → sensorineural hearing loss (inferred).
  10. → Chondrocytes / skeletal tissue → spondylo-epiphyseal dysplasia (inferred).
  11. Loss of NMNAT1's NAD⁺-independent chaperone/proteostasis function may additionally compromise neuronal maintenance — inferred from invertebrate/in-vitro data (F002, F013, F016).

Mechanistic detail

Molecular pathway. NAD⁺ biosynthesis (KEGG hsa00760 nicotinamide/nicotinate metabolism; Reactome NAD biosynthesis): NMN/NaMN + ATP → NAD⁺, catalyzed by NMNAT1, feeding PARP1 (DNA repair) and sirtuin/SIRT1 signaling (F011, F013). NMNAT1 "catalyzes the final step in NAD+ biosynthesis and represents the major nuclear isoform of the mammalian NMNAT family," and NAD⁺ "supports redox reactions, DNA repair, chromatin regulation, stress adaptation, inflammation, and neuronal maintenance" (PMID: 42646333) (F013).

Protein dysfunction. NMNAT1 (UniProt Q9HAN9) is a 279-amino-acid nuclear homohexameric enzyme (PDB 1KKU) that forms NAD⁺ from NMN + ATP (and deamido-NAD⁺ from NaMN), physically interacts with PARP1, and localizes to the nucleus (GO:0005634) (F011). Hypomorphic alleles reduce enzyme dosage rather than abolishing activity; NMNAT1 also "acts as a chaperone that protects against neuronal activity-induced degeneration" (PMID: 22842229).

Cellular processes & tissue damage. The demonstrated process is oxidative DNA damage → apoptosis: "reduced NMNAT1 enzyme function due to the p.V9M mutation leads to DNA damage in PRs, characterized by the progressive accumulation of the oxidative DNA adduct 8-oxo-dG" preceding apoptotic photoreceptor loss (PMID: 41922335) (F003). NMNAT1 dysfunction is more broadly linked to "aging-associated genomic instability, neuroinflammation, synaptic impairment, retinal degeneration" (PMID: 42646333) (F013).

Why photoreceptors first? NMNAT1 is ubiquitously expressed, yet reduced function preferentially injures photoreceptors — implicating their exceptionally high metabolic and NAD⁺ demand and light-driven oxidative load (F003).

Ontology suggestions

  • GO biological process: NAD biosynthetic process (GO:0009435); nicotinamide-nucleotide adenylyltransferase activity (GO:0000309); DNA repair; apoptotic process.
  • GO cellular component: nucleus (GO:0005634).
  • CL cell types: retinal photoreceptor cell (CL:0000210); cochlear hair cell (CL:0000202); oligodendrocyte (CL:0000128); chondrocyte (CL:0000138); neuron (CL:0000540).
  • CHEBI: NAD⁺ (CHEBI:57540); NMN (CHEBI:16171); ATP (CHEBI:30616); deamido-NAD⁺/NaAD (CHEBI:18304).

7. Anatomical Structures Affected

Organ level. - Primary: eye/retina, inner ear/cochlea, central nervous system (cerebrum, cerebellum, white matter), skeleton (vertebral column, long-bone epiphyses). - Body systems: nervous (CNS + special senses), musculoskeletal, sensory (visual, auditory).

Tissue and cell level (F012).

Structure UBERON Affected cell type CL term
Retina / photoreceptor layer UBERON:0000966 Retinal photoreceptor cell CL:0000210
Cochlea / inner ear UBERON:0001844 Cochlear hair cell CL:0000202
Cerebral white matter UBERON:0002316 Oligodendrocyte CL:0000128
Cerebellum UBERON:0002037 Neuron CL:0000540
Vertebral column UBERON:0001130 Chondrocyte CL:0000138
Epiphysis of long bones UBERON:0000958 Chondrocyte CL:0000138

Subcellular level. The primary compartment is the nucleus (GO:0005634), where NMNAT1 synthesizes NAD⁺ and interacts with PARP1 (F011). Downstream oxidative DNA damage affects nuclear genomic DNA.

Localization / lateralization. Retinal degeneration is bilateral with pronounced central (macular) involvement, coalescing into a central scar (PMID: 39710161) (F008). CNS involvement is diffuse/bilateral (leukoencephalopathy, cerebral/cerebellar hypoplasia); skeletal involvement is generalized/axial (platyspondyly, epiphyseal) (F012).

8. Temporal Development

Onset. Congenital. The retinal phenotype is present at birth (Leber congenital amaurosis), and skeletal, auditory, and neurodevelopmental features manifest in infancy (F008, F012, F015).

Progression (ocular). A distinctive triphasic course: congenital severe deficit → rapid progression with atrophic lesions coalescing into a central scar by age 2 → stabilization around age 4 (PMID: 39710161) (F008). This pattern distinguishes NMNAT1-LCA from many other LCA genotypes.

Progression (systemic). Intellectual disability, hearing loss, and skeletal dysplasia are chronic, lifelong, non-remitting. Hypomyelinating leukoencephalopathy and cerebellar hypoplasia imply ongoing neurological morbidity (F012, F015).

Patterns. No spontaneous or treatment-induced remission. The ocular critical window for intervention is the first years of life, before photoreceptor loss is complete — relevant to the stabilization-by-age-4 natural history and to gene-therapy timing (F008, F005).

9. Inheritance and Population

Epidemiology. Ultra-rare. Approximately four patients from three families have been reported worldwide (three original Italian patients plus one Spanish patient) (F001, F006). No reliable prevalence/incidence figures exist; it is below Orphanet's reporting thresholds. The extreme rarity is explained by the requirement for two ultra-rare deleterious hypomorphic alleles (F009).

Inheritance. Autosomal recessive, with full penetrance for the biallelic genotypes described. Reported genotypes: homozygous partial duplication (consanguineous/shared-haplotype Italian families) and compound heterozygous duplication + splice variant (F001, F006). Recurrence risk for carrier couples is 25% per pregnancy (F015).

Penetrance / expressivity. The syndromic SHILCA genotypes are penetrant. By contrast, the common NMNAT1 allele p.E257K is incompletely penetrant (PMID: 24830548), and the overall allelic series shows wide expressivity (isolated LCA → cone-rod dystrophy → HSP → syndromic SHILCA), governed by residual enzyme activity (F004).

Founder effects / consanguinity. The original Italian families shared an identical haplotype across a 4.76 Mb autozygous region, consistent with a shared ancestral allele / consanguinity-related homozygosity (F001). No broad founder population is defined.

Carrier frequency. For deleterious SHILCA alleles, carrier frequency is essentially unmeasurable (private variants not in gnomAD). The common hypomorph p.E257K has a carrier frequency of ~1/485, but this allele alone does not cause SHILCA (F009).

Demographics. Reported patients are of European (Italian, Spanish) ancestry; no sex bias is evident (autosomal). Age at report was very young (~2 years) (F006, F015).

10. Diagnostics

Key diagnostic lesson (F014). SHILCA is a WES-negative structural/splice disorder. In the index families, "whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere"; the diagnosis was reached only because "we then determined the transcriptome of patients' fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments" (PMID: 32533184).

Recommended diagnostic pathway. 1. Clinical gestalt — recognize the LCA + sensorineural hearing loss + skeletal dysplasia + intellectual disability combination. 2. Ophthalmic workup — ERG/VEP (undetectable), OCT (outer-retinal disruption, RPE atrophy), fundus autofluorescence, fluorescein angiography (central hypofluorescence with visible choroidal vasculature) (PMID: 39710161) (F008). 3. Brain MRI — hypomyelination/leukoencephalopathy, cerebellar hypoplasia (F012). 4. Skeletal survey — spondylo-epiphyseal dysplasia, platyspondyly (F012). 5. Molecular testing — NMNAT1 sequencing / IRD gene panel first; if negative despite strong phenotype, escalate to WGS (short + long read) and/or fibroblast RNA-seq to detect structural/splice variants (F014).

Biomarkers. No validated circulating biomarker; research assays include reduced NMNAT1 transcript/protein and increased 8-oxo-dG (mechanistic, not clinical) (F003, F014).

Clinical criteria / differential diagnosis. No formal criteria exist. Differentials include other syndromic LCAs and other causes of deaf-blindness with skeletal dysplasia; the distinctive NMNAT1-LCA retinal natural history (central scar by age 2, stabilizing by age 4) plus the specific multisystem combination point to SHILCA.

NCIT terms: Whole Genome Sequencing (C101294); RNA Sequencing (C101295); Whole Exome Sequencing (C101293).

11. Outcome / Prognosis

Overall (F015). SHILCA is a congenital, chronic, non-remitting disorder producing lifelong severe multi-domain disability: profound early blindness, permanent sensorineural deafness, intellectual disability, and skeletal dysplasia (i.e., deaf-blindness plus ID plus motor/skeletal impairment).

Visual prognosis. Profound from birth; "most patients maintained light perception vision or better, with minimal deterioration of visual acuity after the age of 2" (PMID: 39710161) (F015). No meaningful spontaneous visual recovery.

Survival/mortality. Not quantifiable given ~4 reported patients; youngest described at ~age 2, no disease-specific mortality figure. Severe hypomyelinating leukoencephalopathy, hypotonia, and ataxia imply substantial morbidity (F015).

Morbidity / function. Combined sensory (vision + hearing), cognitive, and motor/skeletal disability; high lifelong care dependency.

Prognostic factors. Residual NMNAT1 activity (genotype severity) is the principal determinant of where a patient falls on the allelic spectrum (F004).

12. Treatment

Current standard — supportive only (F015). There is no approved disease-modifying therapy, and "no human trial has yet established efficacy for an NMNAT-1-directed neurological therapy" (PMID: 42646333) (F013). Management is multidisciplinary: - Sensorineural hearing loss: cochlear implants/hearing aids; auditory-verbal therapy (NCIT: Cochlear Implant C16623). - Vision: low-vision/blindness rehabilitation, special education. - Neurodevelopment / hypotonia / ataxia: developmental, physical, occupational, and speech therapy (NCIT: Physical Therapy C15415). - Skeletal dysplasia: orthopedic surveillance and management of spinal/joint disease. - Dental care for irregular dentition. - Genetic counseling (NCIT: Genetic Counseling C15671; Supportive Care C15346).

Advanced / experimental therapeutics (preclinical; F005). - AAV gene augmentation: "Gene Therapy Preserves Retinal Structure and Function in a Mouse Model" of NMNAT1-associated disease, where "no treatment is available" (PMID: 32775493). Photoreceptor-targeted expression is sufficient: "Expression of NMNAT1 in the photoreceptors is sufficient to prevent" degeneration (PMID: 37214313) — defining a photoreceptor-autonomous target. - Antioxidant / DNA-damage-targeted approaches: the 8-oxo-dG oxidative-DNA-damage mechanism was explicitly flagged as "a therapeutic opportunity" (PMID: 41922335). - NAD-pathway strategies: "Current therapeutic approaches include SARM1 inhibitors in clinical trials, gene therapy, and NAD precursor supplementation" (PMID: 42341897) (F005).

Pharmacogenomics. Not applicable (no disease-specific pharmacotherapy).

13. Prevention

Because SHILCA is purely genetic and congenital, primary prevention is not possible by lifestyle/environmental means (F015).

  • Genetic counseling (primary preventive tool): autosomal recessive counseling with 25% sibling recurrence risk; cascade carrier testing once both familial NMNAT1 alleles are identified.
  • Reproductive options: prenatal diagnosis and preimplantation genetic testing for monogenic disease (PGT-M) are available to known carrier couples (F015).
  • Secondary prevention: early ophthalmic, audiologic, neurodevelopmental, and skeletal surveillance to optimize supportive intervention (cochlear implantation, low-vision rehabilitation, early developmental therapy) within critical developmental windows.
  • Tertiary prevention: orthopedic monitoring to prevent/limit complications of spondylo-epiphyseal dysplasia; management of leukoencephalopathy-related morbidity.
  • Immunization / public-health / environmental interventions: not applicable.

NCIT: Genetic Counseling (C15671).

14. Other Species / Natural Disease

Taxonomy and orthologs (F016). NMNAT1 is deeply conserved:

Species NCBI Taxon Gene NCBI Gene ID
Human 9606 NMNAT1 64802
Mouse 10090 Nmnat1 66454
Zebrafish 7955 nmnat1 —
Drosophila 7227 Nmnat/CG13645 —

The NMNAT enzyme family is conserved to yeast (F016).

Natural disease. No naturally occurring animal equivalent of SHILCA is cataloged in OMIA — all animal disease models are engineered (F016). No companion-animal or wildlife natural counterpart, and no zoonotic/cross-species transmission applies.

Comparative biology / conserved neuroprotection. NMNAT's neuroprotective role is evolutionarily conserved. In Drosophila, "in vivo neuronal expression of mutated nmnat shows that enzymatically inactive NMNAT protein retains strong neuroprotective effects and rescues the degeneration phenotype caused by loss of nmnat" (PMID: 17132048) — evidence for an NAD⁺-independent chaperone function. In mammals, the WldS fusion (Ube4b–Nmnat1) delays axon degeneration, and "increased Nmnat activity is responsible for the axon-sparing activity of the Wlds protein," with increased nuclear NAD biosynthesis and SIRT1 activation preventing axonal degeneration (PMID: 15310905) (F016).

15. Model Organisms

Mouse models (primary; F007).

Model Phenotype Interpretation
Nmnat1 germline knockout Embryonic lethal Complete loss incompatible with life → SHILCA requires hypomorphic allele (F002)
Nmnat1^E257K/E257K knock-in No morphologic/functional retinal defect to 1 yr, even after light damage E257K is a weak, reduced-penetrance hypomorph (PMID: 29674119)
Nmnat1^E257K/− compound het Photoreceptor defects, exacerbated by light Demonstrates dosage-dependence & gene–environment (light) interaction
Retina-specific conditional KO Photoreceptor degeneration before terminal differentiation NMNAT1 needed for retinal development and maintenance
AAV-NMNAT1 gene therapy Preserves retinal structure/function Proof-of-concept therapy (PMID: 32775493)
Photoreceptor-specific NMNAT1 expression Prevents degeneration Photoreceptor-autonomous target (PMID: 37214313)
p.V9M model 8-oxo-dG accumulation → apoptosis Oxidative DNA-damage mechanism (PMID: 41922335)

Invertebrate models. Drosophila Nmnat mutants cause rapid activity-dependent neurodegeneration; enzymatically inactive NMNAT still rescues, demonstrating a chaperone function (PMID: 17132048) (F016).

Model characteristics & limitations. Mouse models recapitulate the retinal (ocular) component of SHILCA well and have validated both mechanism (oxidative DNA damage) and therapy (gene augmentation). However, no published model recapitulates the full multisystem SHILCA phenotype (skeletal dysplasia + hearing loss + leukoencephalopathy together); modeling to date has focused on the retina (F007, F016). Dosage is critical — null alleles are lethal, so SHILCA modeling requires hypomorphic/conditional strategies.

Resources: MGI (mouse Nmnat1, Gene 66454); FlyBase (Nmnat); ZFIN (nmnat1).

Mechanistic Model (Synthesis)

 Biallelic hypomorphic NMNAT1 variants
 (Alu-mediated partial duplication ± splice variant; germline, AR)
    │  demonstrated (RNA-seq ~4x downregulation; WGS)
    ▼
 Reduced NMNAT1 enzyme dosage  ──(residual activity preserved;
    │                      complete loss = embryonic lethal)
    ▼
 Decreased NUCLEAR NAD+ biosynthesis (NMN + ATP → NAD+)
    │  demonstrated biochemically
    ▼
 Impaired PARP1 DNA repair  +  reduced SIRT1 redox/stress adaptation   [inferred]
    ▼
 Accumulation of oxidative DNA damage (8-oxo-dG)   [demonstrated in photoreceptors]
    ▼
 Apoptosis of metabolically demanding, long-lived cells
   ├── Photoreceptors ........ Leber congenital amaurosis   [demonstrated]
   ├── Neurons/oligodendrocytes .. ID, leukoencephalopathy, cerebellar hypoplasia [inferred]
   ├── Cochlear hair cells ... sensorineural hearing loss   [inferred]
   └── Chondrocytes .......... spondylo-epiphyseal dysplasia [inferred]

The retinal arm of this chain is experimentally established end-to-end; the extra-ocular arms are mechanistically plausible extrapolations of the same NAD⁺-deficiency logic applied to cells with high metabolic demand and limited renewal.

Evidence Base

PMID Title (abbrev.) Contribution
32533184 Alu-mediated duplication in NMNAT1 causes SHILCA Defines the disease; identifies the Alu-mediated partial duplication; establishes WES-negative, RNA-seq+WGS diagnosis (F001, F002, F014)
33668384 New insights on the genetic basis of SHILCA Second independent patient; compound-het splice + duplication; replicates full phenotype (F006)
22842229 NMNAT1 mutations cause LCA with macular/optic atrophy Establishes NMNAT1 as LCA9 gene; nuclear enzyme + chaperone role (F002, F011)
41922335 / 40501637 Oxidative DNA damage drives apoptotic photoreceptor loss Mechanism: 8-oxo-dG accumulation → apoptosis; therapeutic opportunity (F003)
24830548 Nonpenetrance of most frequent NMNAT1 LCA mutation p.E257K most common (35.8%), incompletely penetrant; allele-frequency logic (F004, F009)
36871412 NMNAT1 and hereditary spastic paraplegia Extends allelic series beyond retina (F004)
29184169 NMNAT1 variants cause cone/cone-rod dystrophy Broadens ocular allelic spectrum (F004)
30004997 Milder later-onset NMNAT1 retinopathy Milder end of spectrum; genotype–severity link (F004)
39710161 Natural history of NMNAT1-LCA Ocular natural history: rapid progression → stabilizes ~age 4 (F008, F015)
29674119 NMNAT1 E257K mouse model Dosage-dependence; E257K homozygotes asymptomatic; light exacerbation (F007)
32775493 Gene therapy preserves retina in mouse model AAV gene augmentation proof-of-concept (F005)
37214313 NMNAT1 in photoreceptors sufficient to prevent degeneration Photoreceptor-autonomous therapeutic target (F005, F007)
42341897 Programmed axon degeneration gene variants NAD-pathway/SARM1 therapeutic landscape (F005)
42646333 NMNAT1 and NAD review (2026) NMNAT1 as terminal nuclear NAD+ enzyme; no proven human therapy (F013)
17132048 Drosophila NMNAT maintains neural integrity Conserved, NAD+-independent neuroprotection (F016)
15310905 Nuclear NAD biosynthesis + SIRT1 prevent axon degeneration Mammalian conservation of neuroprotective NAD+ mechanism (F016)

Evidence-type caveat. Several SHILCA/NMNAT1 citation snippets were flagged [mismatch] during validation (e.g., the exact variant-nomenclature quotes from PMID 33668384 and the NMNAT1-review quotes from PMID 42646333). The underlying claims are consistent with the papers' reported findings, but the verbatim snippets should be re-verified against the published abstracts before being entered as exact quotes in a knowledge base.

Limitations and Knowledge Gaps

  1. Extreme rarity (n ≈ 4). All clinical knowledge derives from ~4 patients in 3 families. Penetrance, expressivity, full phenotypic range, prognosis, survival, and natural history of the extra-ocular features are essentially uncharacterized.
  2. Extra-ocular mechanism is inferred, not demonstrated. The oxidative-DNA-damage → apoptosis chain is proven only in photoreceptors. Its application to chondrocytes, cochlear hair cells, and oligodendrocytes is a reasonable but untested extrapolation.
  3. No multisystem model. All animal models capture the retinal phenotype; none recapitulates the skeletal, auditory, and leukoencephalopathy triad simultaneously.
  4. No validated clinical biomarker or formal diagnostic criteria; diagnosis relies on expert gestalt plus escalated genomic testing.
  5. No human therapeutic evidence. Gene therapy and NAD-pathway strategies are preclinical/retina-focused; none addresses the systemic disease.
  6. Genotype–phenotype rules are incomplete. Why specific hypomorphic combinations yield syndromic SHILCA versus isolated LCA9 is not quantitatively defined (residual-activity thresholds are hypothesized, not measured per allele).
  7. Citation-snippet mismatches (above) require manual verification.

Proposed Follow-up Experiments / Actions

  1. International patient registry / GeneMatcher outreach — aggregate additional SHILCA cases to define phenotype frequencies, natural history of extra-ocular features, and prognosis.
  2. Allele-resolved enzymatic assays — quantify residual NMNAT1 activity/NAD⁺ output for each hypomorphic allele (duplication, splice, E257K, V9M) to test the residual-activity-threshold model of genotype–phenotype correlation.
  3. Multisystem mouse model — generate hypomorphic/compound-heterozygous Nmnat1 alleles matching patient genotypes (e.g., humanized duplication) and phenotype the skeleton, cochlea, and brain, not just the retina.
  4. Mechanistic validation in extra-ocular cell types — measure nuclear NAD⁺, PARP1 activity, and 8-oxo-dG in patient-derived iPSC-chondrocytes, otic organoids, and oligodendrocytes to test whether the retinal mechanism generalizes.
  5. Therapeutic testing of NAD⁺ precursors ± SARM1 inhibition — assess whether systemic NAD⁺ boosting (NR/NMN) or SARM1 inhibition mitigates extra-ocular degeneration in a multisystem model; the retina-focused AAV strategy cannot reach skeleton/CNS equally.
  6. Diagnostic protocol dissemination — publish/endorse a tiered algorithm (IRD panel → WGS short+long read → fibroblast RNA-seq) so that WES-negative SHILCA cases are reliably solved.
  7. Verify flagged citation snippets against source abstracts (PMID 33668384, 37214313, 42646333) before knowledge-base entry.

Prepared from 16 confirmed findings across 5 investigation iterations and 39 reviewed papers. Evidence spans human clinical case reports, mouse/Drosophila model organism studies, in-vitro biochemistry, and computational/population-genetic data.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 15
Quoted claims found in source 14
Quoted claims not found in source 1
References weighed for topical relevance 18
On topic 12
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:41922335: "a therapeutic opportunity"
  • Text part not found as substring: 'a therapeutic opportunity'

Term Validation

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

Outcome Count
Terms checked 41
Resolved 39
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 35
Terms named correctly 5
Terms named as a different term 21
Terms whose name is worth a second look 9

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:

  • MONDO:0031007 (2 mentions) - the report calls it "MONDO"; MONDO calls it spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis
  • DOID:0112290 (1 mention) - the report calls it "DOID"; DOID calls it spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual developmental disorder, and Leber congenital amaurosis
  • HP:0030512 (1 mention) - the report calls it "Clinical sign (ophthalmic)"; HP calls it Difficulty adjusting to changes in luminance
  • HP:0000546 (1 mention) - the report calls it "Clinical sign"; HP calls it Retinal degeneration
  • HP:0007401 (1 mention) - the report calls it "Clinical sign"; HP calls it Macular atrophy
  • HP:0000648 (1 mention) - the report calls it "Clinical sign"; HP calls it Optic atrophy
  • HP:0000639 (1 mention) - the report calls it "Clinical sign"; HP calls it Nystagmus
  • HP:0000540 (1 mention) - the report calls it "Lab/refractive"; HP calls it Hypermetropia
  • HP:0000407 (1 mention) - the report calls it "Clinical sign"; HP calls it Sensorineural hearing impairment
  • HP:0001249 (1 mention) - the report calls it "Behavioral/cognitive"; HP calls it Intellectual disability
  • HP:0002655 (1 mention) - the report calls it "Physical/skeletal"; HP calls it Spondyloepiphyseal dysplasia
  • HP:0002188 (1 mention) - the report calls it "Imaging/neurologic"; HP calls it Delayed CNS myelination
  • HP:0002352 (1 mention) - the report calls it "Imaging/neurologic"; HP calls it Leukoencephalopathy
  • HP:0006872 (1 mention) - the report calls it "Imaging"; HP calls it Cerebral hypoplasia
  • HP:0001272 (1 mention) - the report calls it "Imaging"; HP calls it Cerebellar atrophy
  • HP:0001252 (1 mention) - the report calls it "Clinical sign"; HP calls it Hypotonia
  • HP:0001251 (1 mention) - the report calls it "Clinical sign"; HP calls it Ataxia
  • HP:0005280 (1 mention) - the report calls it "Dysmorphic"; HP calls it Depressed nasal bridge
  • HP:0000154 (1 mention) - the report calls it "Dysmorphic"; HP calls it Wide mouth
  • UBERON:0000966 (1 mention) - the report calls it "Retina / photoreceptor layer"; UBERON calls it retina
  • UBERON:0000958 (1 mention) - the report calls it "Epiphysis of long bones"; UBERON calls it medulla of organ

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:0001263 (1 mention) - the report calls it "Behavioral/cognitive"; HP calls it Global developmental delay, and lists "Cognitive delay" among its other names
  • HP:0000164 (1 mention) - the report calls it "Dental"; HP calls it Abnormality of the dentition, and lists "Dental problem" among its other names
  • GO:0005634 (3 mentions) - the report calls it "GO cellular component: nucleus"; GO calls it nucleus**, and lists "cell nucleus" among its other names
  • GO:0009435 (1 mention) - the report calls it "GO biological process: NAD biosynthetic process"; GO calls it NAD+ biosynthetic process**, and lists "oxidized NAD biosynthetic process" among its other names
  • CL:0000210 (2 mentions) - the report calls it "CL cell types: retinal photoreceptor cell", "Retinal photoreceptor cell"; CL calls it photoreceptor cell**
  • CL:0000202 (2 mentions) - the report calls it "Cochlear hair cell"; CL calls it auditory hair cell
  • CHEBI:57540 (1 mention) - the report calls it "CHEBI: NAD⁺"; CHEBI calls it NAD(1-)**, and lists "NAD(+)" among its other names
  • UBERON:0001844 (1 mention) - the report calls it "Cochlea / inner ear"; UBERON calls it cochlea, and lists "cochlear organ" among its other names
  • UBERON:0002316 (1 mention) - the report calls it "Cerebral white matter"; UBERON calls it white matter, and lists "neuronal white matter" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • CL:0000210 - called "CL cell types:** retinal photoreceptor cell", "Retinal photoreceptor cell"

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.