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

Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) encodes a DNA helicase that is pivotal in transcriptional regulation, DNA damage response, and ribosomal quality control. Bi-allelic ASCC3 variants have been recently associated with a wide spectrum of non-lethal neuromuscular and neurodevelopmental disorders, with no consistent brain malformations or endocrine dysfunction. We describe a severe lethal form of ASCC3 disease: eight individuals of three consanguineous Bedouin families presented with a consistent phenotype of severe global developmental delay, axial hypotonia, and hypoplasia of the corpus callosum, lethal in infancy. Shared dysmorphic features included narrow palpebral fissures, a sunken flat nasal bridge with a short nasal tip and anteverted nares, and low-set ears. Congenital hypothyroidism was evident in most affected individuals, and all males had micropenis/cryptorchidism. Linkage analysis identified a chromosome 6q16.3 locus segregating within the families consistent with autosomal recessive inheritance (maximum multipoint LOD score: 3.1). Whole-exome sequencing followed by segregation analysis identified within this locus a single disease-associated variant: ASCC3 c.3061T>A (GenBank: NM_006828.4) (p.Phe1021Ile). The phenotype, consistent across all affected individuals, significantly broadens the phenotypic spectrum of ASCC3-related disorders, with unique dysmorphism, previously unreported agenesis of the corpus callosum, micropenis/cryptorchidism, congenital hypothyroidism (possibly relevant to ASCC3's pituitary and thyroid expression and its thyroid hormone receptor interacting protein 4 [TRIP4] interaction), and early lethality.