<i>ACTB</i> deletions or single-nucleotide loss-of-function variants: expansion and further delineation of the phenotype and review of the literature.

Abstract

Pathogenic gain-of-function or dominant-negative effect missense variations in <i>ACTB</i> are associated with a neurodevelopmental disorder characterised by intellectual disability (ID), seizures, sensorineural hearing loss, cerebral, renal and ocular abnormalities and dysmorphic features (Baraitser-Winter cerebrofrontofacial syndrome). <i>ACTB</i> encodes beta-actin, a highly conserved protein involved in cell motility, structure and integrity. Deletions including <i>ACTB,</i> and, more rarely, single-nucleotide loss-of-function variants in <i>ACTB</i> have been described in patients with a distinct phenotype including developmental delay, ID, microcephaly, growth restriction, cardiac and renal abnormalities and dysmorphic features. We collected 14 individuals and 1 fetus carrying a heterozygous deletion including <i>ACTB</i>, and 4 individuals with a heterozygous truncating variant. Genotypic and phenotypic data were analysed. Furthermore, a comprehensive review of all cases reported to date was also undertaken. Twelve out of 17 individuals presented with ID, and 3 out of 17 with learning disabilities. Speech delay and behavioural abnormalities were observed in 15 out of 17 and 12 out of 17 individuals, respectively, motor delay in 9 out of 17 and growth restriction in 9 out of 18. Most of the individuals (13/18) had recognisable dysmorphic features. 11 anomalies were de novo, except for 1 deletion inherited from the mother. The size of the deletion varied from 125 kb to 1.6 Mb and could result from a fork stalling and template switching. This study allowed us to better characterise the phenotype associated with the haploinsufficiency of <i>ACTB,</i> underlying the high prevalence of neurodevelopmental disorders (ID, speech and motor delay, behavioural abnormalities) and growth restriction in this recognisable syndrome.