Three recessive mutations in the sodium leak channel, nonselective (NALCN) have been reported to cause intellectual disability and hypotonia. In addition, 14 de novo heterozygous mutations have been identified in 15 patients with arthrogryposis and neurodevelopmental impairment. Here, we report three patients with neurodevelopmental disease and hypotonia, harboring one recurrent (p.R1181Q) and two novel mutations (p.L312V and p.V1020F) occurring de novo in NALCN. Mutation p.L312 is located in the pore forming S6 region of domain I and p.V1020F in the S5 region of domain III. Mutation p.R1181Q is in a linker region. Mapping these three mutations to a model of NALCN showed p.Leu312 and p.Val1020 positioned in the hydrophobic core of the pore modules, indicating these two mutations may affect the gating function of NALCN. Although p.R1181Q is unlikely to affect the ion channel structure, previous studies have shown that an analogous mutation in Caenorhabditis elegans produced a phenotype with a coiling locomotion, suggesting that p.R1181Q could also affect NALCN function. Our three patients showed profound intellectual disability and growth delay, facial dysmorphologies and hypotonia. The present data support previous work suggesting heterozygous NALCN mutations lead to syndromic neurodevelopmental impairment.

No abstract

BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

No abstract

No abstract