Abstract
We report two rare homozygous variants, including a recurrent missense and intronic variant, in the EIF3K gene in four unrelated individuals with global developmental delay, microcephaly, proportionate short stature, dysmorphic craniofacial features, digit flexion deformities, and the cardiac anomaly, patent ductus arteriosus. Three individuals, who were all of Puerto Rican descent, were homozygous for the NM_013234.3:c.128A>G; p.(Asp43Gly) variant in EIF3K and homozygous for a missense variant in SYNE4 (NM_001039876.2:c.355C>T; p.(Arg119Trp)). SYNE4 is associated with autosomal recessive bilateral sensorineural hearing loss, which was also reported in these probands. Analysis of our dataset confirmed these EIF3K and SYNE4 variants were in linkage disequilibrium in affected individuals, suggesting a possible common ancestor and founder event. A fourth individual from Egypt harbored the homozygous intronic variant c.355-13A>G in EIF3K, which segregated with the phenotype in the family and led to aberrant splicing of EIF3K pre-mRNAs, as shown by insertion of 12 intronic base pairs, skipping of 2 exons, and significantly reduced EIF3K protein levels in skin fibroblasts. Through genetic and functional approaches, we suggest that biallelic EIF3K variants are associated with an autosomal recessive syndromic neurodevelopmental disorder with growth retardation, microcephaly, congenital heart defect, and other anomalies.