ClinVar

This variant is classified as a variant of unknown significance because its contribution to Tessadori-Bicknell-van Haaften neurodevelopmental syndrome (see 619758) has not been confirmed.

In a 16-year-old boy (P7) with a neurodevelopmental disorder, Tessadori et al. (2022) identified a de novo heterozygous c.122G-A transition (c.122G-A, NM_003539.4) in the H4C4 gene, resulting in an arg41-to-his (R41H) substitution at a conserved residue in the core globular domain. The variant, which was found by exome sequencing, was not present in the gnomAD database. Expression of the mutation in zebrafish embryos induced severe developmental defects, suggesting that it is pathogenic. The authors postulated a dominant effect. The patient had poor overall growth, global developmental delay, mild motor delay, speech delay, and moderate intellectual disability. Other features included feeding difficulties, brachycephaly, smooth philtrum, and epicanthal folds. Brain imaging showed cochlear abnormalities and arhinencephaly. Hearing and vision were normal. The authors also referred to this mutation as ARG40HIS (R40H), reflecting the practice of dropping the numbering of the first posttranslationally removed methionine.