A lethal form of ASCC3 disease: severe global developmental delay, axial hypotonia, hypoplasia of corpus callosum, hypothyroidism and micropenis

Biallelic *ASCC3* (DNA helicase) missense variant causing a severe lethal neurodevelopmental disorder

Eight individuals from three consanguineous Bedouin families presented with a previously undescribed lethal form of ASCC3-related disease: severe global developmental delay, axial hypotonia, corpus callosum hypoplasia, and childhood lethality, with shared dysmorphic features. Congenital hypothyroidism was present in most, and all males had micropenis/cryptorchidism. Linkage analysis identified a 6q16.3 locus (maximum multipoint LOD 3.1) consistent with recessive inheritance, and exome sequencing revealed a single ASCC3 variant c.3061T>A, p.Phe1021Ile. This phenotype substantially expands the spectrum of ASCC3-related disorders, previously described as non-lethal and without brain malformation or endocrine dysfunction.

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The phenotypic expansion of ASCC3 toward a lethal form with endocrine involvement and brain malformation is clinically striking and useful for counseling consanguineous families. Correlation with ASCC3 pituitary/thyroid expression and its TRIP4 interaction offers a plausible mechanistic lead. A single shared missense variant strengthens the founder effect but does not yet allow broad genotype-phenotype correlation.