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(Used a dyadic nomenclature used for disease name, similar to how the ID GCEP names these syndromes. Lumped the 2 OMIM phenotypes Hypomyelinating neuropathy, congenital, 3 and Lethal congenital contracture syndrome 7).
(Used a dyadic nomenclature used for disease name, similar to how the ID GCEP names these syndromes. Lumped the 2 OMIM phenotypes Hypomyelinating neuropathy, congenital, 3 and Lethal congenital contracture syndrome 7).
CASE SERIES: Severe congenital hypomyelinating neuropathy. Common clinical features: Polyhydramnios resulting in prematurity, hypotonia, respiratory distress at birth, demyelinating/hypomyelinating neuropathy, reduced white matter bulk and cerebral atrophy, facial features including myopathic facies.
Patient 2: c.1677G>A p.W559* - 9 alleles gnomAD v4, low enough for AR disease. NMD+. comp het with Leu212Pro (5 alleles total gnomAD v4, REVEL: 0.802). Phenotype - growth deficiency (low weight, height, OFC centiles), profound ID, central hypotonia, orobulbar dysfunction, peripheral myopathy, abnormal brain MRI (lack of myelination, reduced white matter, atrophic cerebellum), SNHL, pectus excavatum, neonatal respiratory distress, trach, scoliosis, hip subluxation, myopathic faces, cathedral palate. SEGREGATES IN AFFECTED SIB (1 AR SEG)2.5 VARIANT POINTS
Patient 4: HOM for Arg782Ter (13/1179948 Euro alleles gAD v4, low enough for AR disease), similar pheno to proband 2. 4 VARIANT POINTS
Patient 5: Cmp het for 1735+1G>A (5 alleles total gAD v4) and Arg782Ter. Similar phenotype. 4 VARIANT POINTS
Patient 6: Comp het for c.149C>A p.Pro50Gln (1 allele total gAD v4) ;, c.2600del Asp867fs (5 alleles total, NMD+. 2.5 VARIANT POINTS
PMID: 27159321 (2016) - Curating for replication and phenotype (didn’t score variants).
LD_0158 HOM for p.Arg388Pro, per supplement case summary, respiratory failure, bilateral HL, cleft palate, hypomyelinating neuropathy, delayed myelination and cerebral atrophy.
Both of these individuals also reported in 29882456 (2018) where phenotype includes arthrogryposis (indicating the arthrogryposis and hypomyelinating phenotypes should be lumped (both LOF variants reported). Additional features included arthrogryposis multiplex congenita, cortical vision loss, neurogenic bladder, seizures,
PMID: 33820833 (2022)
Patients 37-42 in supplement with variants in CNTNAP1. Arthrogryposis multiplex congenita cohort. Phenotype: identified prenatally, postnatal death <1 month for 5/6 individuals, hypotonia,
Clinical ValidityPoints Total
13
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
Definitive
Source:
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Loss of function
See clinical validity scoring, >3 LOF variants
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Congenital
Severity
Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
Clinical Features
Polyhydramnios resulting in prematurity, significant hypotonia, neonatal respiratory insufficiency, demyelinating/hypomyelinating neuropathy, abnormal brain MRI (delayed myelination, reduced white matter, cerebellar atrophy, cerebral atrophy), arthrogryposis multiplex congenita or contractures, feeding difficulties, facial features including myopathic facies, hearing loss, and intellectual disability (PMID: 29511323, 27159321, 33820833.
- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited
The CNTNAP1 gene is associated with autosomal recessive CNTNAP1-related complex neurodevelopmental syndrome. This is a complex syndrome with many clinical features. Commonly observed features include polyhydramnios resulting in prematurity, significant hypotonia, neonatal respiratory insufficiency, demyelinating/hypomyelinating neuropathy, abnormal brain MRI (delayed myelination, reduced white matter, cerebellar atrophy, cerebral atrophy), arthrogryposis multiplex congenita or contractures, feeding difficulties, facial features including myopathic facies, hearing loss, and intellectual disability (PMID: 29511323, 27159321, 33820833).