Bi-allelic FRA10AC1 variants in a multisystem human syndrome.

Abstract

We read the recent article by von Elsner et al.1 with interest. The authors described five individuals from three families with homozygous FRA10AC1 variants, neurodevelopmental delay, intellectual disability, brain abnormalities, microcephaly, growth impairment and craniofacial dysmorphisms. Here, we report findings that support the conclusions reached by von Elsner and colleagues, and provide further insights into this novel disorder. Parents of all participating individuals provided informed consent according to the Declaration of Helsinki and The Central Manchester NHS Research Ethics Committees approved this study (02/CM/238). We ascertained two sisters born to consanguineous parents with global developmental delay, growth impairment, congenital malformations and facial dysmorphism overlapping that of Kabuki syndrome2,3 (OMIM 147920) (Fig. 1A and Table 1). In two affected and one unaffected sibling we performed autozygosity mapping as described previously4 and identified two regions of >2 Mb length that were homozygous only in the affected individuals (Supplementary Table 1). Whole exome sequencing of affected individuals as described previously,5 followed by segregation studies of candidate variants within the linked regions revealed a nonsense FRA10AC1 NM_145246.5:c.328C > T (p.Arg110Ter) variant as the likely cause for the phenotype (Fig. 1B). In gnomAD, there are no homozygous predicted loss of function (pLOF) FRA10AC1 variants, although heterozygous pLOF variants are present at a frequency of ∼1/2000. Next, we identified an individual in the DECIPHER database (257391) with a ∼13 kb homozygous deletion involving a part of FRA10AC1 and no other known gene (Fig. 1A and B). Characterization of the deletion by PCR and Sanger sequencing of genomic DNA (Supplementary material) revealed the variant to be an in-del consisting of a 12 721 bp deletion (Chr10:93 695 674–93 708 393; GRCh38.p12) and a 10 bp duplication. The 5′ breakpoint of the variant was in the intergenic region between FRA10AC1 and LGI1. The 3′ breakpoint was in the intron 4 of FRA10AC1. The duplicated sequence (TTAGTACACA) was a repeat of the first 10 bp of sequence downstream of the variant. The deletion results in loss of the 5′ untranslated region and first four exons of FRA10AC1. Reverse transcription-PCR of RNA extracted from fibroblasts from this patient, revealed absence of FRA10AC1 transcripts (Fig. 1C). Although the individual was ascertained due to her genotype, reverse phenotyping6 revealed her clinical features to overlap significantly with those of the affected individuals in Family 1 (Table 1).1 Collectively, these data provide evidence that bi-allelic pLOF FRA10AC1 variants cause a human developmental disorder.