HECW2 – Neurodevelopmental Disorder with Hypotonia, Seizures, and Absent Language

HECW2 variants have been implicated in Neurodevelopmental Disorder with Hypotonia, Seizures, and Absent Language ([PMID:37280227]). To date, two unrelated probands with NDHSAL have been described: one with a de novo missense change, c.4343>C (p.Leu1448Ser), presenting with congenital long QT syndrome ([PMID:37280227]), and a second with a homozygous splice‐disrupting variant causing exon 22 skipping (p.Leu1256_Trp1306del) in a consanguineous family ([PMID:35753050]). No additional affected relatives with segregating variants have been reported.

Functional analysis of the homozygous splicing variant revealed a twofold increase in transcript levels and a 60% reduction in HECW2 protein expression, consistent with partial loss of function ([PMID:35753050]). While HECW2’s role as an E3 ubiquitin ligase for p73 and other nuclear proteins is established, in vivo models recapitulating NDHSAL are lacking. Overall, current evidence supports a limited clinical validity for HECW2 in NDHSAL. Further segregation analyses and in vivo functional studies are required to establish definitive causality. Key take‐home: HECW2 variants underlie both de novo dominant and rare recessive forms of NDHSAL, but existing data remain insufficient for definitive diagnostic use.

References

• Human genome variation • 2023 • A novel HECW2 variant in an infant with congenital long QT syndrome. PMID:37280227
• Human mutation • 2022 • First splicing variant in HECW2 with an autosomal recessive pattern of inheritance and associated with NDHSAL. PMID:35753050

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