Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- intrafamilial variability. has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping genotyping five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome 2). In addition to homozygous causal in ASPM CENPJ, we discovered heterozygous modifier WDR62, CEP63, RAD50 PCNT—genes already known associated neurological disorders. patients carrying an variant showed more severe phenotypic features. Likewise, phenotype caused by a novel CENPJ was aggravated microcephalic osteodysplastic primordial dwarfism type II (MOPDII) conjunction PCNT variant. show missense impairs splicing decreases protein expression. also observed centrosome amplification errors patient cells, which were twofold higher MOPDII compared cells. Taken together, these observations advocate consideration related genes their role modifying expressivity need considered counseling risk assessment.