oa OFD1 Missense Mutation Causes an Autosomal Recessive Dyskeratosis Congenita-Like Disorder Further Complicating the Clinical Heterogeneity of OFD1 Mutations

A consanguineous [first cousin marriage] family of Arabic ethnic origin with four unaffected siblings and two male siblings affected by a Dyskeratosis Congenita-like disorder, was studied by Genome-Wide SNP homozygosity mapping, functional and positional candidate gene screening by Sanger sequencing, and Whole Genome Sequencing [WGS] to identify the offending gene and mutation. The disorder is marked by short stature, sparse hair including eyelashes, leukoplakia, dental carries and early tooth loss, osteoporosis, skin atrophy and hyper pigmentation, nail dystrophy with longitudinal ridging and splitting without bone marrow involvement.

The offending gene was mapped to two possible homozygous genomic regions on chromosomes 3p and 6q cumulatively spanning 24 Mb containing 86 protein-coding genes. Functional and positional candidate gene screening by Sanger sequencing for ARL6IP, BCKDHB, DKC1, DNAH17, EEF1A1, LRIG1, ORC3, POLA1, SLC17A5 and SYNCRIP did not identify causative pathogenic mutations. Analyses and mining of WGS data for homozygous variants within the homozygous regions and Xlinked variants [as only males are affected] in X-shared regions among affected siblings, identified a homozygous missense c.C2353T/p.P785S mutation in the OFD1 gene, at Xp22.2. The mutation co-segregates with the disease phenotype within the family, is absent in all public databases and in 500 ethnically matched control chromosomes. OFD1 is a 1012 aa protein component of centrioles, controlling centriole length and involved in cilium biogenesis. OFD1 mutations cause Oral-facial-digital syndrome 1, Simpson-Golabi-Behmel Syndrome Type 2, Joubert Syndrome 10 and Retinitis Pigmentosa 23 displaying significant phenotypic heterogeneity and clinical variability. The c.C2353T/p.P785S mutation ads a Dyskeratosis Congenita-like phenotype to the wide spectrum of OFD1 disease phenotypes. In addition, it demonstrates that when applying WGS data to clinical diagnoses, all significant variants should be considered and scrutinized for their clinical impact, irrespective of the observed clinical presentation.