Cornelia de Lange syndrome

Genetic MONDO:0016033 Pathograph 21 cohesinopathy multiple congenital anomaly syndrome syndromic intellectual disability

Cornelia de Lange syndrome is a rare multiple-congenital-anomalies syndrome caused by pathogenic variants in cohesin-complex structural or regulatory genes, most commonly NIPBL. Disrupted cohesin loading, chromatin organization, and RNA polymerase II transcriptional regulation alter developmental gene expression programs, producing characteristic craniofacial features, hypertrichosis, growth restriction, limb malformations, intellectual disability, feeding and reflux problems, hearing impairment, and variable visceral malformations.

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1
Mappings
1
Definitions
2
Inheritance
6
Pathophys.
34
Phenotypes
21
Pathograph
7
Genes
2
Treatments
1
Differentials
5
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0016033 Cornelia de Lange syndrome
skos:exactMatch Orphanet ORPHA:199
Orphanet ORPHA:199 lists MONDO:0016033 as an exact cross-reference for Cornelia de Lange syndrome.
📘

Definitions

1
Orphanet Cornelia de Lange syndrome definition
A rare multiple-congenital-anomalies syndrome characterized by facial dysmorphism, hypertrichosis, intellectual disability, antenatal and/or postnatal growth restriction, feeding difficulties, hand and foot abnormalities, and variable visceral malformations.
OTHER
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"A rare multiple congenital anomalies syndrome characterized by facial dysmorphism, hypertrichosis, mild to profound intellectual disability, intrauterine growth restriction (IUGR) and/or postnatal growth restriction, feeding difficulties, abnormalities of the hands and feet"
Orphanet defines the core congenital, neurodevelopmental, growth, and limb phenotype pattern.
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Many CdLS cases are autosomal dominant, often due to de novo pathogenic variants, although familial transmission can occur.
Autosomal dominant inheritance De novo rate: Most molecularly confirmed NIPBL cases with informative parental testing
Show evidence (2 references)
ORPHA:199 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for CdLS.
PMID:26701315 SUPPORT Human Clinical
"All mutations shown to have arisen de novo when parent blood samples were available."
This NIPBL case series supports predominantly de novo occurrence when parental samples are informative.
X-linked inheritance HP:0001417
Some CdLS molecular subtypes involve X-linked cohesin pathway genes.
X-linked inheritance
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"X-linked recessive"
Orphanet records an X-linked inheritance mode for CdLS.
⚙

Pathophysiology

6
Cohesin pathway gene disruption
CdLS is caused by pathogenic variants in genes encoding cohesin structural proteins or regulators, including NIPBL, SMC1A, SMC3, RAD21, HDAC8, and BRD4. NIPBL encodes the delangin/cohesin-loading factor, and many cases are driven by reduced dosage or impaired function of this pathway.
NIPBL link SMC1A link SMC3 link RAD21 link HDAC8 link BRD4 link
sister chromatid cohesion link ↓ DECREASED chromatin organization link ↓ DECREASED
Downstream
Impaired cohesin loading and chromatin organization Pathogenic variants reduce or alter cohesin structural/regulatory functions required for normal chromatin binding and organization.
Show evidence (3 references)
ORPHA:199 SUPPORT Other
"NIPBL | NIPBL cohesin loading factor | hgnc:28862 | Disease-causing germline mutation(s) in"
Orphanet identifies NIPBL as a disease-causing germline CdLS gene.
PMID:29995837 SUPPORT Human Clinical
"It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex."
The international consensus statement frames CdLS as a cohesin structural/regulatory gene disorder.
PMID:15146186 SUPPORT Human Clinical
"We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS."
The original gene discovery paper identifies NIPBL mutations in sporadic and familial CdLS.
Impaired cohesin loading and chromatin organization
NIPBL facilitates cohesin loading and cohesin binding to regulatory regions. CdLS-associated NIPBL or cohesin subunit dysfunction perturbs cohesin binding, chromatin regulatory architecture, and enhancer/promoter control.
NIPBL link SMC1A link SMC3 link
chromatin organization link ↓ DECREASED
chromatin binding link ↓ DECREASED transcription cis-regulatory region binding link ↓ DECREASED
Downstream
Developmental transcriptional dysregulation Altered cohesin loading and regulatory-region binding changes expression of developmental genes in CdLS cells and models.
Show evidence (2 references)
PMID:15146185 SUPPORT Human Clinical
"Vertebrate delangins have substantial homology to orthologs in flies, worms, plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B."
NIPBL/delangin homology links the disease gene to cohesin-loading biology.
PMID:19468298 SUPPORT In Vitro
"Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of a boundary/insulator interacting protein."
Human CdLS cell-line analyses support cohesin cis-regulatory binding defects.
Developmental transcriptional dysregulation
Human CdLS cell lines and Nipbl-deficient model systems show widespread modest transcriptional changes whose aggregate effects perturb embryonic development. Cohesin can affect RNA polymerase II initiation and elongation, providing a mechanistic link from cohesin gene variants to multisystem developmental phenotypes.
regulation of transcription by RNA polymerase II link ↓ DECREASED epigenetic regulation of gene expression link ↓ DECREASED embryo development link ↓ DECREASED
Downstream
Craniofacial and limb morphogenesis abnormalities Dysregulated developmental gene expression perturbs facial, skeletal, and limb morphogenesis.
Growth and neurodevelopmental impairment Widespread transcriptional perturbation disrupts growth and neural developmental programs.
Feeding and visceral malformations Multisystem developmental gene dysregulation contributes to GI, cardiac, renal, and other visceral manifestations.
Show evidence (3 references)
PMID:19468298 SUPPORT In Vitro
"Genome-wide assessment of transcription in 16 mutant cell lines from severely affected CdLS probands has identified a unique profile of dysregulated gene expression that was validated in an additional 101 samples and correlates with phenotypic severity."
Human CdLS cell-line transcriptome dysregulation correlates with clinical severity.
PMID:26581180 SUPPORT In Vitro
"altered transcriptional initiation and elongation caused transcription dysregulation in genes whose SMC1A binding was increased."
SMC1A-mutant CdLS cells show impaired RNA polymerase II transcription regulation.
PMID:19763162 SUPPORT Model Organism
"Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS"
Nipbl haploinsufficient mice recapitulate CdLS-like multisystem defects.
Craniofacial and limb morphogenesis abnormalities
CdLS shows a recognizable craniofacial gestalt and upper-limb/hand-foot malformations, including synophrys, thick eyebrows, long eyelashes, micrognathia, small hands, micromelia, and oligodactyly.
embryo development link ↓ DECREASED
Downstream
Synophrys Synophrys is part of the recognizable CdLS facial gestalt.
Micromelia Limb morphogenesis disruption produces micromelia and related hand-foot abnormalities.
Oligodactyly Limb morphogenesis disruption can produce reductional limb defects including oligodactyly.
Show evidence (2 references)
ORPHA:199 SUPPORT Other
"facial dysmorphism, hypertrichosis, mild to profound intellectual disability, intrauterine growth restriction (IUGR) and/or postnatal growth restriction, feeding difficulties, abnormalities of the hands and feet"
Orphanet defines facial dysmorphism and hand/foot abnormalities as core CdLS manifestations.
PMID:15146185 PARTIAL Human Clinical
"We propose that perturbed delangin function may inappropriately activate DLX genes, thereby contributing to the proximodistal limb patterning defects in CdLS."
The NIPBL discovery paper links delangin dysfunction to limb patterning defects.
Growth and neurodevelopmental impairment
Disrupted cohesin-regulated developmental transcription contributes to antenatal and postnatal growth restriction, microcephaly, intellectual disability, speech impairment, tone abnormalities, autism, anxiety, and other neurobehavioral manifestations.
embryo development link ↓ DECREASED
Downstream
Intrauterine growth retardation Growth-program disruption causes antenatal growth restriction.
Short stature Growth-program disruption causes postnatal short stature.
Intellectual disability Neurodevelopmental transcriptional disruption contributes to intellectual disability.
Show evidence (2 references)
PMID:29995837 SUPPORT Human Clinical
"Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms."
The international consensus identifies intellectual disability and atypical growth as core CdLS features.
PMID:19763162 SUPPORT Model Organism
"We propose that the aggregate effects of many small transcriptional changes are the cause of developmental abnormalities of CdLS"
The Nipbl mouse model supports cumulative transcriptional effects as a cause of developmental abnormalities.
Feeding and visceral malformations
CdLS commonly includes feeding difficulties and gastroesophageal reflux, and can include renal, genital, cardiac, diaphragmatic, intestinal, and other visceral malformations.
Downstream
Feeding difficulties in infancy Multisystem developmental disruption contributes to feeding difficulty.
Gastroesophageal reflux GI developmental and motility disturbance contributes to reflux.
Ventricular septal defect Developmental disruption can produce congenital heart defects including VSD.
Show evidence (2 references)
ORPHA:199 SUPPORT Other
"Variable visceral malformations may be present."
Orphanet records variable visceral malformations in CdLS.
PMID:15146186 SUPPORT Human Clinical
"gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features."
The original NIPBL paper summarizes GI, cardiac, eye, and genitourinary CdLS anomalies.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cornelia de Lange 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.
●

Phenotypes

34
Cardiovascular 1
Ventricular septal defect OCCASIONAL Ventricular septal defect (HP:0001629)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0001629 | Ventricular septal defect | Occasional (29-5%)"
Orphanet records ventricular septal defect as an occasional CdLS phenotype.
Digestive 2
Feeding difficulties in infancy FREQUENT Feeding difficulties in infancy (HP:0008872)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0008872 | Feeding difficulties in infancy | Frequent (79-30%)"
Orphanet records feeding difficulties in infancy as frequent in CdLS.
Gastroesophageal reflux VERY_FREQUENT Gastroesophageal reflux (HP:0002020)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0002020 | Gastroesophageal reflux | Very frequent (99-80%)"
Orphanet records gastroesophageal reflux as very frequent in CdLS.
Ear 2
Hearing impairment FREQUENT Hearing impairment (HP:0000365)
Show evidence (2 references)
ORPHA:199 SUPPORT Other
"HP:0000405 | Conductive hearing impairment | Frequent (79-30%)"
Orphanet records conductive hearing impairment as frequent in CdLS.
ORPHA:199 SUPPORT Other
"HP:0000407 | Sensorineural hearing impairment | Frequent (79-30%)"
Orphanet records sensorineural hearing impairment as frequent in CdLS.
Atresia of the external auditory canal VERY_FREQUENT Atresia of the external auditory canal (HP:0000413)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000413 | Atresia of the external auditory canal | Very frequent (99-80%)"
Orphanet records atresia of the external auditory canal as very frequent in CdLS.
Head and Neck 11
Brachycephaly VERY_FREQUENT Brachycephaly (HP:0000248)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000248 | Brachycephaly | Very frequent (99-80%)"
Orphanet records brachycephaly as very frequent in CdLS.
Microcephaly VERY_FREQUENT Microcephaly (HP:0000252)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000252 | Microcephaly | Very frequent (99-80%)"
Orphanet records microcephaly as very frequent in CdLS.
Micrognathia VERY_FREQUENT Micrognathia (HP:0000347)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000347 | Micrognathia | Very frequent (99-80%)"
Orphanet records micrognathia as very frequent in CdLS.
High palate VERY_FREQUENT High palate (HP:0000218)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000218 | High palate | Very frequent (99-80%)"
Orphanet records high palate as very frequent in CdLS.
Long philtrum VERY_FREQUENT Long philtrum (HP:0000343)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000343 | Long philtrum | Very frequent (99-80%)"
Orphanet records long philtrum as very frequent in CdLS.
Short nose VERY_FREQUENT Short nose (HP:0003196)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0003196 | Short nose | Very frequent (99-80%)"
Orphanet records short nose as very frequent in CdLS.
Depressed nasal bridge VERY_FREQUENT Depressed nasal bridge (HP:0005280)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0005280 | Depressed nasal bridge | Very frequent (99-80%)"
Orphanet records depressed nasal bridge as very frequent in CdLS.
Anteverted nares VERY_FREQUENT Anteverted nares (HP:0000463)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000463 | Anteverted nares | Very frequent (99-80%)"
Orphanet records anteverted nares as very frequent in CdLS.
Short neck VERY_FREQUENT Short neck (HP:0000470)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000470 | Short neck | Very frequent (99-80%)"
Orphanet records short neck as very frequent in CdLS.
Highly arched eyebrow VERY_FREQUENT Highly arched eyebrow (HP:0002553)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0002553 | Highly arched eyebrow | Very frequent (99-80%)"
Orphanet records highly arched eyebrow as very frequent in CdLS.
Delayed eruption of teeth VERY_FREQUENT Delayed eruption of teeth (HP:0000684)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000684 | Delayed eruption of teeth | Very frequent (99-80%)"
Orphanet records delayed eruption of teeth as very frequent in CdLS.
Limbs 4
Micromelia VERY_FREQUENT Micromelia (HP:0002983)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0002983 | Micromelia | Very frequent (99-80%)"
Orphanet records micromelia as very frequent in CdLS.
Small hand VERY_FREQUENT Small hand (HP:0200055)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0200055 | Small hand | Very frequent (99-80%)"
Orphanet records small hand as very frequent in CdLS.
Toe syndactyly VERY_FREQUENT Toe syndactyly (HP:0001770)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0001770 | Toe syndactyly | Very frequent (99-80%)"
Orphanet records toe syndactyly as very frequent in CdLS.
Short foot VERY_FREQUENT Short foot (HP:0001773)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0001773 | Short foot | Very frequent (99-80%)"
Orphanet records short foot as very frequent in CdLS.
Musculoskeletal 2
Hypertonia VERY_FREQUENT Hypertonia (HP:0001276)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0001276 | Hypertonia | Very frequent (99-80%)"
Orphanet records hypertonia as very frequent in CdLS.
Delayed skeletal maturation VERY_FREQUENT Delayed skeletal maturation (HP:0002750)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0002750 | Delayed skeletal maturation | Very frequent (99-80%)"
Orphanet records delayed skeletal maturation as very frequent in CdLS.
Nervous System 5
Intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)
Show evidence (2 references)
ORPHA:199 SUPPORT Other
"HP:0001249 | Intellectual disability | Very frequent (99-80%)"
Orphanet records intellectual disability as very frequent in CdLS.
PMID:29995837 SUPPORT Human Clinical
"characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth"
The international consensus lists intellectual disability among core CdLS features.
Anxiety FREQUENT Anxiety (HP:0000739)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000739 | Anxiety | Frequent (79-30%)"
Orphanet records anxiety as frequent in CdLS.
Compulsive behaviors FREQUENT Compulsive behaviors (HP:0000722)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000722 | Compulsive behaviors | Frequent (79-30%)"
Orphanet records compulsive behaviors as frequent in CdLS.
Attention deficit hyperactivity disorder FREQUENT Attention deficit hyperactivity disorder (HP:0007018)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0007018 | Attention deficit hyperactivity disorder | Frequent (79-30%)"
Orphanet records attention deficit hyperactivity disorder as frequent in CdLS.
Sleep abnormality FREQUENT Sleep disturbance (HP:0002360)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0002360 | Sleep abnormality | Frequent (79-30%)"
Orphanet records sleep abnormality as frequent in CdLS.
Growth 2
Intrauterine growth retardation FREQUENT Intrauterine growth retardation (HP:0001511)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0001511 | Intrauterine growth retardation | Frequent (79-30%)"
Orphanet records intrauterine growth retardation as frequent in CdLS.
Short stature VERY_FREQUENT Short stature (HP:0004322)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0004322 | Short stature | Very frequent (99-80%)"
Orphanet records short stature as very frequent in CdLS.
Other 5
Synophrys VERY_FREQUENT Synophrys (HP:0000664)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000664 | Synophrys | Very frequent (99-80%)"
Orphanet records synophrys as very frequent in CdLS.
Thick eyebrow VERY_FREQUENT Thick eyebrow (HP:0000574)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0000574 | Thick eyebrow | Very frequent (99-80%)"
Orphanet records thick eyebrow as very frequent in CdLS.
Downturned corners of mouth VERY_FREQUENT Downturned corners of mouth (HP:0002714)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0002714 | Downturned corners of mouth | Very frequent (99-80%)"
Orphanet records downturned corners of mouth as very frequent in CdLS.
Generalized hirsutism VERY_FREQUENT Generalized hirsutism (HP:0002230)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0002230 | Generalized hirsutism | Very frequent (99-80%)"
Orphanet records generalized hirsutism as very frequent in CdLS.
Oligodactyly OCCASIONAL Oligodactyly (HP:0012165)
Show evidence (1 reference)
ORPHA:199 SUPPORT Other
"HP:0012165 | Oligodactyly | Occasional (29-5%)"
Orphanet records oligodactyly as an occasional CdLS phenotype.
🧬

Genetic Associations

7
NIPBL germline pathogenic variants
Show evidence (4 references)
ORPHA:199 SUPPORT Other
"NIPBL | NIPBL cohesin loading factor | hgnc:28862 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline NIPBL mutations in CdLS.
PMID:15146186 SUPPORT Human Clinical
"Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder"
The original NIPBL discovery paper describes CdLS as a dominantly inherited multisystem developmental disorder.
PMID:26581180 SUPPORT Human Clinical
"About 70% of CdLS patients have heterozygous mutations in NIPBL, the majority being truncating (haploinsufficient), and these types of mutations are often associated with severe phenotypes"
This supports NIPBL as the major molecular cause and links truncating NIPBL variants with severe CdLS phenotypes.
+ 1 more reference
De novo NIPBL pathogenic variants
Show evidence (2 references)
PMID:26701315 SUPPORT Human Clinical
"Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation."
This NIPBL cohort characterizes CdLS as mainly related to de novo heterozygous NIPBL mutation.
PMID:26701315 SUPPORT Human Clinical
"All mutations shown to have arisen de novo when parent blood samples were available."
Parent-sample testing in this series supports de novo occurrence for identified NIPBL variants.
NIPBL somatic mosaicism
Show evidence (2 references)
PMID:23505322 SUPPORT Human Clinical
"In 10 of the 13 tested individuals without detectable mutation in lymphocytes a NIPBL mutation could be detected in buccal cells."
Buccal-cell testing detected NIPBL variants in clinically diagnosed patients without lymphocyte findings.
PMID:23505322 SUPPORT Human Clinical
"Somatic mosaicism for an NIPBL mutation is frequent (10/44; 23%) clinically in reliably diagnosed CdLS individuals."
This supports somatic mosaicism as a clinically important CdLS genetic mechanism.
Other cohesin pathway genes
Show evidence (4 references)
ORPHA:199 SUPPORT Other
"SMC1A | structural maintenance of chromosomes 1A | hgnc:11111 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline SMC1A mutations in CdLS.
ORPHA:199 SUPPORT Other
"HDAC8 | histone deacetylase 8 | hgnc:13315 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet records loss-of-function HDAC8 mutations in CdLS.
PMID:29995837 SUPPORT Human Clinical
"It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex."
The consensus statement supports genetic heterogeneity within the cohesin pathway.
+ 1 more reference
HDAC8 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_a7d29159-4c90-488e-a4e1-b006d70ae762-2018-09-10T220000.000Z SUPPORT Other
"HDAC8 | HGNC:13315 | Cornelia de Lange syndrome | MONDO:0016033 | XL | Definitive"
ClinGen classifies the HDAC8-Cornelia de Lange syndrome gene-disease relationship as definitive with X-linked inheritance.
RAD21 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_30ad5023-6c68-42ab-b8ea-a601a134eaf6-2020-01-08T170000.000Z SUPPORT Other
"RAD21 | HGNC:9811 | Cornelia de Lange syndrome | MONDO:0016033 | AD | Definitive"
ClinGen classifies the RAD21-Cornelia de Lange syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
SMC3 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_9467eaad-a86a-4b24-8cd4-98ebb57121c1-2020-04-07T160000.000Z SUPPORT Other
"SMC3 | HGNC:2468 | Cornelia de Lange syndrome | MONDO:0016033 | AD | Definitive"
ClinGen classifies the SMC3-Cornelia de Lange syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Treatments

2
Multidisciplinary supportive care
Action: supportive care MAXO:0000950
CdLS management is supportive and multidisciplinary, addressing growth, feeding, reflux, hearing, vision, neurodevelopmental, behavioral, orthopedic, cardiac, renal, and other system-specific needs.
Show evidence (1 reference)
PMID:29995837 SUPPORT Human Clinical
"clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning."
The international consensus provides long-term management and care-planning recommendations.
Genetic counseling and molecular testing
Action: genetic counseling MAXO:0000079
Molecular testing helps confirm CdLS and guides recurrence-risk counseling, including consideration of de novo, autosomal dominant, X-linked, and mosaic presentations.
Show evidence (3 references)
PMID:29995837 SUPPORT Human Clinical
"next-generation sequencing have improved molecular diagnostics"
Consensus guidance supports molecular diagnostic testing as part of CdLS care.
ORPHA:199 SUPPORT Other
"Autosomal dominant"
Documented heritable modes support genetic counseling for recurrence risk.
PMID:23505322 SUPPORT Human Clinical
"Obtaining buccal swabs at the time a blood sample is obtained will facilitate adequate molecular analysis of clinically diagnosed CdLS patients."
Buccal swab testing improves detection when mosaic NIPBL variants are not found in blood-derived DNA.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Cornelia de Lange syndrome:

Bohring-Opitz syndrome MONDO:0011510
Overlapping Features Bohring-Opitz syndrome can overlap with CdLS through growth restriction, intellectual disability, feeding difficulties, hypertrichosis, and craniofacial features, but it is typically ASXL1-related and has a distinct posture and tumor-surveillance considerations.
Distinguishing Features
  • ASXL1-related chromatin disorder rather than a primary cohesinopathy.
  • Characteristic Bohring-Opitz posture is not a core CdLS feature.
Show evidence (1 reference)
PMID:25921057 SUPPORT Human Clinical
"Bohring-Opitz syndrome posture is characterized by flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints."
This supports a distinguishing Bohring-Opitz feature relevant to CdLS differential diagnosis.
{ }

Source YAML

click to show 
name: Cornelia de Lange syndrome
category: Genetic
creation_date: '2026-05-04T02:04:04Z'
updated_date: '2026-05-04T02:04:04Z'
synonyms:
- CdLS
- Brachmann-de Lange syndrome
description: >
  Cornelia de Lange syndrome is a rare multiple-congenital-anomalies syndrome
  caused by pathogenic variants in cohesin-complex structural or regulatory
  genes, most commonly NIPBL. Disrupted cohesin loading, chromatin organization,
  and RNA polymerase II transcriptional regulation alter developmental gene
  expression programs, producing characteristic craniofacial features,
  hypertrichosis, growth restriction, limb malformations, intellectual
  disability, feeding and reflux problems, hearing impairment, and variable
  visceral malformations.
disease_term:
  preferred_term: Cornelia de Lange syndrome
  term:
    id: MONDO:0016033
    label: Cornelia de Lange syndrome
parents:
- cohesinopathy
- multiple congenital anomaly syndrome
- syndromic intellectual disability
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016033
      label: Cornelia de Lange syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:199
    mapping_justification: >
      Orphanet ORPHA:199 lists MONDO:0016033 as an exact cross-reference for
      Cornelia de Lange syndrome.
external_assertions:
- name: Orphanet Cornelia de Lange syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:199
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=199
  description: >
    Orphanet's ORPHA:199 structured record provides the exact MONDO and OMIM
    mappings, inheritance, definition, epidemiology, disease-gene assertions,
    and HPO phenotype rows used in this curation.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0016033 | Exact"
    explanation: Orphanet maps ORPHA:199 exactly to the MONDO identifier used here.
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:122470 | Exact"
    explanation: Orphanet maps ORPHA:199 exactly to the classic autosomal dominant OMIM CdLS record.
definitions:
- name: Orphanet Cornelia de Lange syndrome definition
  definition_type: OTHER
  description: >
    A rare multiple-congenital-anomalies syndrome characterized by facial
    dysmorphism, hypertrichosis, intellectual disability, antenatal and/or
    postnatal growth restriction, feeding difficulties, hand and foot
    abnormalities, and variable visceral malformations.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare multiple congenital anomalies syndrome characterized by facial dysmorphism, hypertrichosis, mild to profound intellectual disability, intrauterine growth restriction (IUGR) and/or postnatal growth restriction, feeding difficulties, abnormalities of the hands and feet"
    explanation: Orphanet defines the core congenital, neurodevelopmental, growth, and limb phenotype pattern.
inheritance:
- name: Autosomal dominant inheritance
  description: >
    Many CdLS cases are autosomal dominant, often due to de novo pathogenic
    variants, although familial transmission can occur.
  de_novo_rate: Most molecularly confirmed NIPBL cases with informative parental testing
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for CdLS.
  - reference: PMID:26701315
    reference_title: "A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All mutations shown to have arisen de novo when parent blood samples were available."
    explanation: This NIPBL case series supports predominantly de novo occurrence when parental samples are informative.
- name: X-linked inheritance
  description: Some CdLS molecular subtypes involve X-linked cohesin pathway genes.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "X-linked recessive"
    explanation: Orphanet records an X-linked inheritance mode for CdLS.
prevalence:
- population: Europe
  percentage: 1-9 per 100,000 births
  notes: Orphanet records European prevalence at birth in the rare-disease range.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Europe | Prevalence at birth | PMID:18074387"
    explanation: Orphanet records European prevalence at birth for CdLS.
progression:
- phase: Antenatal and neonatal onset
  age_range: Antenatal to neonatal
  notes: >
    Growth restriction and congenital anomalies can be evident antenatally or
    neonatally, while developmental, feeding, hearing, behavioral, and visceral
    complications require ongoing pediatric and adult care.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Antenatal"
    explanation: Orphanet records antenatal onset for CdLS.
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset for CdLS.
pathophysiology:
- name: Cohesin pathway gene disruption
  description: >
    CdLS is caused by pathogenic variants in genes encoding cohesin structural
    proteins or regulators, including NIPBL, SMC1A, SMC3, RAD21, HDAC8, and
    BRD4. NIPBL encodes the delangin/cohesin-loading factor, and many cases are
    driven by reduced dosage or impaired function of this pathway.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NIPBL | NIPBL cohesin loading factor | hgnc:28862 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies NIPBL as a disease-causing germline CdLS gene.
  - reference: PMID:29995837
    reference_title: "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex."
    explanation: The international consensus statement frames CdLS as a cohesin structural/regulatory gene disorder.
  - reference: PMID:15146186
    reference_title: "Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS."
    explanation: The original gene discovery paper identifies NIPBL mutations in sporadic and familial CdLS.
  genes:
  - preferred_term: NIPBL
    term:
      id: hgnc:28862
      label: NIPBL
  - preferred_term: SMC1A
    term:
      id: hgnc:11111
      label: SMC1A
  - preferred_term: SMC3
    term:
      id: hgnc:2468
      label: SMC3
  - preferred_term: RAD21
    term:
      id: hgnc:9811
      label: RAD21
  - preferred_term: HDAC8
    term:
      id: hgnc:13315
      label: HDAC8
  - preferred_term: BRD4
    term:
      id: hgnc:13575
      label: BRD4
  biological_processes:
  - preferred_term: sister chromatid cohesion
    term:
      id: GO:0007062
      label: sister chromatid cohesion
    modifier: DECREASED
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: DECREASED
  downstream:
  - target: Impaired cohesin loading and chromatin organization
    causal_link_type: DIRECT
    description: >
      Pathogenic variants reduce or alter cohesin structural/regulatory
      functions required for normal chromatin binding and organization.
- name: Impaired cohesin loading and chromatin organization
  description: >
    NIPBL facilitates cohesin loading and cohesin binding to regulatory regions.
    CdLS-associated NIPBL or cohesin subunit dysfunction perturbs cohesin
    binding, chromatin regulatory architecture, and enhancer/promoter control.
  evidence:
  - reference: PMID:15146185
    reference_title: "NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertebrate delangins have substantial homology to orthologs in flies, worms, plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B."
    explanation: NIPBL/delangin homology links the disease gene to cohesin-loading biology.
  - reference: PMID:19468298
    reference_title: "Transcriptional dysregulation in NIPBL and cohesin mutant human cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of a boundary/insulator interacting protein."
    explanation: Human CdLS cell-line analyses support cohesin cis-regulatory binding defects.
  genes:
  - preferred_term: NIPBL
    term:
      id: hgnc:28862
      label: NIPBL
  - preferred_term: SMC1A
    term:
      id: hgnc:11111
      label: SMC1A
  - preferred_term: SMC3
    term:
      id: hgnc:2468
      label: SMC3
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: DECREASED
  molecular_functions:
  - preferred_term: chromatin binding
    term:
      id: GO:0003682
      label: chromatin binding
    modifier: DECREASED
  - preferred_term: transcription cis-regulatory region binding
    term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    modifier: DECREASED
  downstream:
  - target: Developmental transcriptional dysregulation
    causal_link_type: DIRECT
    description: >
      Altered cohesin loading and regulatory-region binding changes expression
      of developmental genes in CdLS cells and models.
- name: Developmental transcriptional dysregulation
  description: >
    Human CdLS cell lines and Nipbl-deficient model systems show widespread
    modest transcriptional changes whose aggregate effects perturb embryonic
    development. Cohesin can affect RNA polymerase II initiation and elongation,
    providing a mechanistic link from cohesin gene variants to multisystem
    developmental phenotypes.
  evidence:
  - reference: PMID:19468298
    reference_title: "Transcriptional dysregulation in NIPBL and cohesin mutant human cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Genome-wide assessment of transcription in 16 mutant cell lines from severely affected CdLS probands has identified a unique profile of dysregulated gene expression that was validated in an additional 101 samples and correlates with phenotypic severity."
    explanation: Human CdLS cell-line transcriptome dysregulation correlates with clinical severity.
  - reference: PMID:26581180
    reference_title: "Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "altered transcriptional initiation and elongation caused transcription dysregulation in genes whose SMC1A binding was increased."
    explanation: SMC1A-mutant CdLS cells show impaired RNA polymerase II transcription regulation.
  - reference: PMID:19763162
    reference_title: "Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS"
    explanation: Nipbl haploinsufficient mice recapitulate CdLS-like multisystem defects.
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  - preferred_term: epigenetic regulation of gene expression
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
    modifier: DECREASED
  - preferred_term: embryo development
    term:
      id: GO:0009790
      label: embryo development
    modifier: DECREASED
  downstream:
  - target: Craniofacial and limb morphogenesis abnormalities
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered expression of developmental regulator genes
    description: >
      Dysregulated developmental gene expression perturbs facial, skeletal, and
      limb morphogenesis.
  - target: Growth and neurodevelopmental impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cumulative subtle changes in growth and neurodevelopmental gene expression programs
    description: >
      Widespread transcriptional perturbation disrupts growth and neural
      developmental programs.
  - target: Feeding and visceral malformations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Multisystem developmental gene dysregulation contributes to GI, cardiac,
      renal, and other visceral manifestations.
- name: Craniofacial and limb morphogenesis abnormalities
  description: >
    CdLS shows a recognizable craniofacial gestalt and upper-limb/hand-foot
    malformations, including synophrys, thick eyebrows, long eyelashes,
    micrognathia, small hands, micromelia, and oligodactyly.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "facial dysmorphism, hypertrichosis, mild to profound intellectual disability, intrauterine growth restriction (IUGR) and/or postnatal growth restriction, feeding difficulties, abnormalities of the hands and feet"
    explanation: Orphanet defines facial dysmorphism and hand/foot abnormalities as core CdLS manifestations.
  - reference: PMID:15146185
    reference_title: "NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that perturbed delangin function may inappropriately activate DLX genes, thereby contributing to the proximodistal limb patterning defects in CdLS."
    explanation: The NIPBL discovery paper links delangin dysfunction to limb patterning defects.
  biological_processes:
  - preferred_term: embryo development
    term:
      id: GO:0009790
      label: embryo development
    modifier: DECREASED
  downstream:
  - target: Synophrys
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Craniofacial developmental-patterning disruption
    description: Synophrys is part of the recognizable CdLS facial gestalt.
  - target: Micromelia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Limb developmental-patterning disruption
    description: Limb morphogenesis disruption produces micromelia and related hand-foot abnormalities.
  - target: Oligodactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Limb developmental-patterning disruption
    description: Limb morphogenesis disruption can produce reductional limb defects including oligodactyly.
- name: Growth and neurodevelopmental impairment
  description: >
    Disrupted cohesin-regulated developmental transcription contributes to
    antenatal and postnatal growth restriction, microcephaly, intellectual
    disability, speech impairment, tone abnormalities, autism, anxiety, and
    other neurobehavioral manifestations.
  evidence:
  - reference: PMID:29995837
    reference_title: "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms."
    explanation: The international consensus identifies intellectual disability and atypical growth as core CdLS features.
  - reference: PMID:19763162
    reference_title: "Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We propose that the aggregate effects of many small transcriptional changes are the cause of developmental abnormalities of CdLS"
    explanation: The Nipbl mouse model supports cumulative transcriptional effects as a cause of developmental abnormalities.
  biological_processes:
  - preferred_term: embryo development
    term:
      id: GO:0009790
      label: embryo development
    modifier: DECREASED
  downstream:
  - target: Intrauterine growth retardation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered developmental gene expression programs
    description: Growth-program disruption causes antenatal growth restriction.
  - target: Short stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered developmental gene expression programs
    description: Growth-program disruption causes postnatal short stature.
  - target: Intellectual disability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered neurodevelopmental gene expression programs
    description: Neurodevelopmental transcriptional disruption contributes to intellectual disability.
- name: Feeding and visceral malformations
  description: >
    CdLS commonly includes feeding difficulties and gastroesophageal reflux,
    and can include renal, genital, cardiac, diaphragmatic, intestinal, and
    other visceral malformations.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Variable visceral malformations may be present."
    explanation: Orphanet records variable visceral malformations in CdLS.
  - reference: PMID:15146186
    reference_title: "Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features."
    explanation: The original NIPBL paper summarizes GI, cardiac, eye, and genitourinary CdLS anomalies.
  downstream:
  - target: Feeding difficulties in infancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Multisystem developmental disruption contributes to feeding difficulty.
  - target: Gastroesophageal reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: GI developmental and motility disturbance contributes to reflux.
  - target: Ventricular septal defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered cardiac developmental gene expression programs
    description: Developmental disruption can produce congenital heart defects including VSD.
phenotypes:
- name: Synophrys
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Synophrys is a very frequent component of the CdLS facial gestalt.
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000664 | Synophrys | Very frequent (99-80%)"
    explanation: Orphanet records synophrys as very frequent in CdLS.
- name: Thick eyebrow
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Thick eyebrows are a very frequent feature of the CdLS facial gestalt.
  phenotype_term:
    preferred_term: Thick eyebrow
    term:
      id: HP:0000574
      label: Thick eyebrow
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000574 | Thick eyebrow | Very frequent (99-80%)"
    explanation: Orphanet records thick eyebrow as very frequent in CdLS.
- name: Brachycephaly
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Brachycephaly is a very frequent head-shape feature in CdLS.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000248 | Brachycephaly | Very frequent (99-80%)"
    explanation: Orphanet records brachycephaly as very frequent in CdLS.
- name: Microcephaly
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Microcephaly is a very frequent cranial and neurodevelopmental CdLS feature.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000252 | Microcephaly | Very frequent (99-80%)"
    explanation: Orphanet records microcephaly as very frequent in CdLS.
- name: Micrognathia
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Micrognathia is a very frequent craniofacial feature in CdLS.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
    explanation: Orphanet records micrognathia as very frequent in CdLS.
- name: High palate
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: High palate is a very frequent oral craniofacial feature in CdLS.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000218 | High palate | Very frequent (99-80%)"
    explanation: Orphanet records high palate as very frequent in CdLS.
- name: Long philtrum
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Long philtrum is a very frequent diagnostic facial gestalt feature.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000343 | Long philtrum | Very frequent (99-80%)"
    explanation: Orphanet records long philtrum as very frequent in CdLS.
- name: Downturned corners of mouth
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Downturned mouth corners are a very frequent facial gestalt feature.
  phenotype_term:
    preferred_term: Downturned corners of mouth
    term:
      id: HP:0002714
      label: Downturned corners of mouth
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002714 | Downturned corners of mouth | Very frequent (99-80%)"
    explanation: Orphanet records downturned corners of mouth as very frequent in CdLS.
- name: Short nose
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Short nose is a very frequent craniofacial feature in CdLS.
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003196 | Short nose | Very frequent (99-80%)"
    explanation: Orphanet records short nose as very frequent in CdLS.
- name: Depressed nasal bridge
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Depressed nasal bridge is a very frequent CdLS facial feature.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005280 | Depressed nasal bridge | Very frequent (99-80%)"
    explanation: Orphanet records depressed nasal bridge as very frequent in CdLS.
- name: Anteverted nares
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Anteverted nares are a very frequent facial gestalt feature in CdLS.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000463 | Anteverted nares | Very frequent (99-80%)"
    explanation: Orphanet records anteverted nares as very frequent in CdLS.
- name: Short neck
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Short neck is a very frequent CdLS feature.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000470 | Short neck | Very frequent (99-80%)"
    explanation: Orphanet records short neck as very frequent in CdLS.
- name: Highly arched eyebrow
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Highly arched eyebrows are a very frequent facial gestalt feature.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002553 | Highly arched eyebrow | Very frequent (99-80%)"
    explanation: Orphanet records highly arched eyebrow as very frequent in CdLS.
- name: Delayed eruption of teeth
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Delayed tooth eruption is a very frequent dental manifestation in CdLS.
  phenotype_term:
    preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000684 | Delayed eruption of teeth | Very frequent (99-80%)"
    explanation: Orphanet records delayed eruption of teeth as very frequent in CdLS.
- name: Generalized hirsutism
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: Generalized hirsutism/hypertrichosis is a very frequent CdLS feature.
  phenotype_term:
    preferred_term: Generalized hirsutism
    term:
      id: HP:0002230
      label: Generalized hirsutism
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002230 | Generalized hirsutism | Very frequent (99-80%)"
    explanation: Orphanet records generalized hirsutism as very frequent in CdLS.
- name: Intellectual disability
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Intellectual disability ranges from mild to profound in CdLS.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
    explanation: Orphanet records intellectual disability as very frequent in CdLS.
  - reference: PMID:29995837
    reference_title: "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth"
    explanation: The international consensus lists intellectual disability among core CdLS features.
- name: Hypertonia
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Hypertonia is a very frequent neurologic manifestation in CdLS.
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001276 | Hypertonia | Very frequent (99-80%)"
    explanation: Orphanet records hypertonia as very frequent in CdLS.
- name: Anxiety
  category: Behavioral
  frequency: FREQUENT
  description: Anxiety is a frequent behavioral manifestation in CdLS.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000739 | Anxiety | Frequent (79-30%)"
    explanation: Orphanet records anxiety as frequent in CdLS.
- name: Compulsive behaviors
  category: Behavioral
  frequency: FREQUENT
  description: Compulsive behaviors are frequent behavioral manifestations in CdLS.
  phenotype_term:
    preferred_term: Compulsive behaviors
    term:
      id: HP:0000722
      label: Compulsive behaviors
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000722 | Compulsive behaviors | Frequent (79-30%)"
    explanation: Orphanet records compulsive behaviors as frequent in CdLS.
- name: Attention deficit hyperactivity disorder
  category: Behavioral
  frequency: FREQUENT
  description: ADHD is a frequent neurobehavioral manifestation in CdLS.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007018 | Attention deficit hyperactivity disorder | Frequent (79-30%)"
    explanation: Orphanet records attention deficit hyperactivity disorder as frequent in CdLS.
- name: Sleep abnormality
  category: Behavioral
  frequency: FREQUENT
  description: Sleep abnormality is a frequent behavioral and neurodevelopmental feature.
  phenotype_term:
    preferred_term: Sleep abnormality
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002360 | Sleep abnormality | Frequent (79-30%)"
    explanation: Orphanet records sleep abnormality as frequent in CdLS.
- name: Intrauterine growth retardation
  category: Growth
  frequency: FREQUENT
  description: Antenatal growth restriction is frequent and can be apparent before birth.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001511 | Intrauterine growth retardation | Frequent (79-30%)"
    explanation: Orphanet records intrauterine growth retardation as frequent in CdLS.
- name: Short stature
  category: Growth
  frequency: VERY_FREQUENT
  description: Postnatal growth restriction and short stature are very frequent in CdLS.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Very frequent (99-80%)"
    explanation: Orphanet records short stature as very frequent in CdLS.
- name: Delayed skeletal maturation
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Delayed skeletal maturation is a very frequent skeletal growth feature.
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002750 | Delayed skeletal maturation | Very frequent (99-80%)"
    explanation: Orphanet records delayed skeletal maturation as very frequent in CdLS.
- name: Micromelia
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Limb shortening is part of the severe end of the CdLS limb-reduction spectrum.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002983 | Micromelia | Very frequent (99-80%)"
    explanation: Orphanet records micromelia as very frequent in CdLS.
- name: Small hand
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Small hands are a very frequent limb manifestation in CdLS.
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200055 | Small hand | Very frequent (99-80%)"
    explanation: Orphanet records small hand as very frequent in CdLS.
- name: Toe syndactyly
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Toe syndactyly is a very frequent distal limb manifestation in CdLS.
  phenotype_term:
    preferred_term: Toe syndactyly
    term:
      id: HP:0001770
      label: Toe syndactyly
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001770 | Toe syndactyly | Very frequent (99-80%)"
    explanation: Orphanet records toe syndactyly as very frequent in CdLS.
- name: Short foot
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Short feet are a very frequent limb manifestation in CdLS.
  phenotype_term:
    preferred_term: Short foot
    term:
      id: HP:0001773
      label: Short foot
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001773 | Short foot | Very frequent (99-80%)"
    explanation: Orphanet records short foot as very frequent in CdLS.
- name: Oligodactyly
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: Reductional limb defects can include missing digits.
  phenotype_term:
    preferred_term: Oligodactyly
    term:
      id: HP:0012165
      label: Oligodactyly
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012165 | Oligodactyly | Occasional (29-5%)"
    explanation: Orphanet records oligodactyly as an occasional CdLS phenotype.
- name: Feeding difficulties in infancy
  category: Gastrointestinal
  frequency: FREQUENT
  description: Feeding difficulty is frequent in infancy and is part of the core care burden.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008872 | Feeding difficulties in infancy | Frequent (79-30%)"
    explanation: Orphanet records feeding difficulties in infancy as frequent in CdLS.
- name: Gastroesophageal reflux
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: Gastroesophageal reflux is a very frequent GI manifestation.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002020 | Gastroesophageal reflux | Very frequent (99-80%)"
    explanation: Orphanet records gastroesophageal reflux as very frequent in CdLS.
- name: Hearing impairment
  category: Sensory
  frequency: FREQUENT
  description: Both conductive and sensorineural hearing impairment are frequent.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000405 | Conductive hearing impairment | Frequent (79-30%)"
    explanation: Orphanet records conductive hearing impairment as frequent in CdLS.
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000407 | Sensorineural hearing impairment | Frequent (79-30%)"
    explanation: Orphanet records sensorineural hearing impairment as frequent in CdLS.
- name: Atresia of the external auditory canal
  category: Sensory
  frequency: VERY_FREQUENT
  description: External auditory canal atresia is a very frequent ENT manifestation in CdLS.
  phenotype_term:
    preferred_term: Atresia of the external auditory canal
    term:
      id: HP:0000413
      label: Atresia of the external auditory canal
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000413 | Atresia of the external auditory canal | Very frequent (99-80%)"
    explanation: Orphanet records atresia of the external auditory canal as very frequent in CdLS.
- name: Ventricular septal defect
  category: Cardiovascular
  frequency: OCCASIONAL
  description: Congenital heart defects can include ventricular septal defect.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001629 | Ventricular septal defect | Occasional (29-5%)"
    explanation: Orphanet records ventricular septal defect as an occasional CdLS phenotype.
genetic:
- name: NIPBL germline pathogenic variants
  gene_term:
    preferred_term: NIPBL
    term:
      id: hgnc:28862
      label: NIPBL
  variant_origin: GERMLINE
  relationship_type: CAUSATIVE
  notes: >
    NIPBL pathogenic variants are the most common known cause of classic CdLS
    and disrupt cohesin loading/regulatory function. Truncating NIPBL variants
    are often associated with severe phenotypes.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NIPBL | NIPBL cohesin loading factor | hgnc:28862 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline NIPBL mutations in CdLS.
  - reference: PMID:15146186
    reference_title: "Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder"
    explanation: The original NIPBL discovery paper describes CdLS as a dominantly inherited multisystem developmental disorder.
  - reference: PMID:26581180
    reference_title: "Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 70% of CdLS patients have heterozygous mutations in NIPBL, the majority being truncating (haploinsufficient), and these types of mutations are often associated with severe phenotypes"
    explanation: This supports NIPBL as the major molecular cause and links truncating NIPBL variants with severe CdLS phenotypes.
  - reference: CGGV:assertion_d4ecc430-6562-4d58-9118-c5253dc95ae9-2025-08-11T100000.000Z
    reference_title: "NIPBL / Cornelia de Lange syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NIPBL | HGNC:28862 | Cornelia de Lange syndrome | MONDO:0016033 | AD | Definitive"
    explanation: ClinGen classifies the NIPBL-Cornelia de Lange syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: De novo NIPBL pathogenic variants
  gene_term:
    preferred_term: NIPBL
    term:
      id: hgnc:28862
      label: NIPBL
  variant_origin: DE_NOVO
  relationship_type: CAUSATIVE
  notes: >
    Most molecularly confirmed NIPBL cases in tested series arise de novo when
    parental samples are informative.
  evidence:
  - reference: PMID:26701315
    reference_title: "A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation."
    explanation: This NIPBL cohort characterizes CdLS as mainly related to de novo heterozygous NIPBL mutation.
  - reference: PMID:26701315
    reference_title: "A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All mutations shown to have arisen de novo when parent blood samples were available."
    explanation: Parent-sample testing in this series supports de novo occurrence for identified NIPBL variants.
- name: NIPBL somatic mosaicism
  gene_term:
    preferred_term: NIPBL
    term:
      id: hgnc:28862
      label: NIPBL
  variant_origin: SOMATIC
  relationship_type: CAUSATIVE
  notes: >
    Postzygotic NIPBL mosaicism can explain clinically diagnosed CdLS with
    negative leukocyte DNA testing; buccal swab DNA can improve molecular
    detection.
  evidence:
  - reference: PMID:23505322
    reference_title: "High rate of mosaicism in individuals with Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 10 of the 13 tested individuals without detectable mutation in lymphocytes a NIPBL mutation could be detected in buccal cells."
    explanation: Buccal-cell testing detected NIPBL variants in clinically diagnosed patients without lymphocyte findings.
  - reference: PMID:23505322
    reference_title: "High rate of mosaicism in individuals with Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic mosaicism for an NIPBL mutation is frequent (10/44; 23%) clinically in reliably diagnosed CdLS individuals."
    explanation: This supports somatic mosaicism as a clinically important CdLS genetic mechanism.
- name: Other cohesin pathway genes
  variant_origin: GERMLINE
  relationship_type: CAUSATIVE
  notes: >
    Non-NIPBL CdLS molecular subtypes involve cohesin structural or regulatory
    genes including SMC1A, SMC3, RAD21, HDAC8, and BRD4. SMC1A-associated CdLS
    is reported with a mild-to-moderate phenotype.
  evidence:
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SMC1A | structural maintenance of chromosomes 1A | hgnc:11111 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline SMC1A mutations in CdLS.
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HDAC8 | histone deacetylase 8 | hgnc:13315 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet records loss-of-function HDAC8 mutations in CdLS.
  - reference: PMID:29995837
    reference_title: "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex."
    explanation: The consensus statement supports genetic heterogeneity within the cohesin pathway.
  - reference: PMID:26581180
    reference_title: "Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in SMC1A have been found in about 5% of CdLS cases and the clinical picture of SMC1A-mutated probands is characterized by a mild-to-moderate phenotype"
    explanation: This supports SMC1A as a non-NIPBL molecular subtype with a milder severity profile.
- name: HDAC8
  gene_term:
    preferred_term: HDAC8
    term:
      id: hgnc:13315
      label: HDAC8
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_a7d29159-4c90-488e-a4e1-b006d70ae762-2018-09-10T220000.000Z
    reference_title: "HDAC8 / Cornelia de Lange syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HDAC8 | HGNC:13315 | Cornelia de Lange syndrome | MONDO:0016033 | XL | Definitive"
    explanation: ClinGen classifies the HDAC8-Cornelia de Lange syndrome gene-disease relationship as definitive with X-linked inheritance.
- name: RAD21
  gene_term:
    preferred_term: RAD21
    term:
      id: hgnc:9811
      label: RAD21
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_30ad5023-6c68-42ab-b8ea-a601a134eaf6-2020-01-08T170000.000Z
    reference_title: "RAD21 / Cornelia de Lange syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RAD21 | HGNC:9811 | Cornelia de Lange syndrome | MONDO:0016033 | AD | Definitive"
    explanation: ClinGen classifies the RAD21-Cornelia de Lange syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: SMC3
  gene_term:
    preferred_term: SMC3
    term:
      id: hgnc:2468
      label: SMC3
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_9467eaad-a86a-4b24-8cd4-98ebb57121c1-2020-04-07T160000.000Z
    reference_title: "SMC3 / Cornelia de Lange syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SMC3 | HGNC:2468 | Cornelia de Lange syndrome | MONDO:0016033 | AD | Definitive"
    explanation: ClinGen classifies the SMC3-Cornelia de Lange syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Multidisciplinary supportive care
  description: >
    CdLS management is supportive and multidisciplinary, addressing growth,
    feeding, reflux, hearing, vision, neurodevelopmental, behavioral,
    orthopedic, cardiac, renal, and other system-specific needs.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:29995837
    reference_title: "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning."
    explanation: The international consensus provides long-term management and care-planning recommendations.
- name: Genetic counseling and molecular testing
  description: >
    Molecular testing helps confirm CdLS and guides recurrence-risk counseling,
    including consideration of de novo, autosomal dominant, X-linked, and
    mosaic presentations.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:29995837
    reference_title: "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "next-generation sequencing have improved molecular diagnostics"
    explanation: Consensus guidance supports molecular diagnostic testing as part of CdLS care.
  - reference: ORPHA:199
    reference_title: "Cornelia de Lange syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Documented heritable modes support genetic counseling for recurrence risk.
  - reference: PMID:23505322
    reference_title: "High rate of mosaicism in individuals with Cornelia de Lange syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Obtaining buccal swabs at the time a blood sample is obtained will facilitate adequate molecular analysis of clinically diagnosed CdLS patients."
    explanation: Buccal swab testing improves detection when mosaic NIPBL variants are not found in blood-derived DNA.
differential_diagnoses:
- name: Bohring-Opitz syndrome
  description: >
    Bohring-Opitz syndrome can overlap with CdLS through growth restriction,
    intellectual disability, feeding difficulties, hypertrichosis, and
    craniofacial features, but it is typically ASXL1-related and has a distinct
    posture and tumor-surveillance considerations.
  disease_term:
    preferred_term: Bohring-Opitz syndrome
    term:
      id: MONDO:0011510
      label: Bohring-Opitz syndrome
  distinguishing_features:
  - ASXL1-related chromatin disorder rather than a primary cohesinopathy.
  - Characteristic Bohring-Opitz posture is not a core CdLS feature.
  evidence:
  - reference: PMID:25921057
    reference_title: "Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bohring-Opitz syndrome posture is characterized by flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints."
    explanation: This supports a distinguishing Bohring-Opitz feature relevant to CdLS differential diagnosis.
references:
- reference: ORPHA:199
  title: Cornelia de Lange syndrome
  findings: []
- reference: PMID:29995837
  title: "Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement."
  findings: []
- reference: PMID:23505322
  title: "High rate of mosaicism in individuals with Cornelia de Lange syndrome."
  findings: []
- reference: PMID:26701315
  title: "A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome."
  findings: []
- reference: PMID:26581180
  title: "Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome."
  findings: []
review_notes: >-
  This entry curates the direct Orphanet leaf disorder ORPHA:199, exact to
  MONDO:0016033. It models CdLS as a cohesinopathy whose primary disease
  mechanism is cohesin regulatory/structural gene disruption causing
  developmental transcriptional dysregulation.
📚

References & Deep Research

References

5
ORPHA:199
Cornelia de Lange syndrome
No top-level findings curated for this source.
PMID:29995837
Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.
No top-level findings curated for this source.
PMID:23505322
High rate of mosaicism in individuals with Cornelia de Lange syndrome.
No top-level findings curated for this source.
PMID:26701315
A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.
No top-level findings curated for this source.
PMID:26581180
Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome.
No top-level findings curated for this source.

Deep Research

1
Manual Fallback ▸
Cornelia de Lange Syndrome Research Fallback

Cornelia de Lange Syndrome Research Fallback

Deep-research provider attempts were made after the ORPHA:199 direct Orphanet/MONDO target was selected:

  • timeout 120 just research-disorder falcon Cornelia_de_Lange_Syndrome
  • timeout 120 just research-disorder openai Cornelia_de_Lange_Syndrome

Both commands printed the initial provider line, then stalled without producing a research output file and were terminated by the timeout. The curation therefore used the structured Orphanet cache plus fetched PubMed cache records as the auditable evidence base.

Literature Scope Checked

  • references_cache/ORPHA_199.md: direct Orphanet leaf record for Cornelia de Lange syndrome, including definition, autosomal dominant and X-linked inheritance, exact MONDO and OMIM mappings, prevalence, age of onset, disease-gene assertions, and HPO phenotype rows.
  • references_cache/PMID_29995837.md: international consensus statement supporting CdLS as a cohesin-complex gene disorder with intellectual disability, facial features, upper-limb anomalies, atypical growth, molecular diagnostics, and long-term management guidance.
  • references_cache/PMID_15146186.md: human NIPBL gene-discovery evidence, including sporadic and familial CdLS cases and multisystem clinical manifestations.
  • references_cache/PMID_15146185.md: NIPBL/delangin gene-discovery evidence connecting Scc2/Nipped-B homolog function to CdLS and limb-patterning defects.
  • references_cache/PMID_23505322.md: human CdLS cohort evidence supporting frequent NIPBL somatic mosaicism and buccal swab DNA testing when blood testing is negative.
  • references_cache/PMID_26701315.md: human NIPBL series supporting de novo heterozygous NIPBL variants, germline and somatic NIPBL mutations, and first-line buccal cell DNA analysis for diagnostic sensitivity.
  • references_cache/PMID_19468298.md: human CdLS cell-line evidence for transcriptional dysregulation, cohesin regulatory-region binding, and phenotype-severity correlation.
  • references_cache/PMID_26581180.md: SMC1A-mutant CdLS cell evidence that mutant cohesin affects RNA polymerase II regulation.
  • references_cache/PMID_19763162.md: Nipbl heterozygous mouse-model evidence for multisystem defects and transcriptional dysregulation consistent with CdLS.
  • references_cache/PMID_25921057.md: clinical management paper used only for the Bohring-Opitz syndrome differential diagnosis.

Curation Conclusions

  • Disease identity is the syndrome-level disorder ORPHA:199, exact to MONDO:0016033 and OMIM:122470.
  • The core disease mechanism is pathogenic variation in cohesin structural or regulatory genes, especially NIPBL, causing impaired cohesin loading, altered chromatin/regulatory-region binding, and developmental transcriptional dysregulation.
  • Orphanet directly supports the curated phenotype profile, including synophrys, thick eyebrows, highly arched eyebrows, brachycephaly, microcephaly, micrognathia, high palate, long philtrum, downturned corners of mouth, short nose, depressed nasal bridge, anteverted nares, short neck, delayed eruption of teeth, generalized hirsutism, intellectual disability, hypertonia, anxiety, compulsive behaviors, attention deficit hyperactivity disorder, sleep abnormality, intrauterine growth retardation, short stature, delayed skeletal maturation, micromelia, small hand, toe syndactyly, short foot, oligodactyly, feeding difficulties, gastroesophageal reflux, hearing impairment, atresia of the external auditory canal, and ventricular septal defect.
  • Evidence-backed management is supportive and multidisciplinary, with genetic counseling and molecular testing supported by the consensus statement, inheritance evidence, and buccal swab testing evidence for mosaic cases.