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Skeletal dysplasias are a clinically and genetically heterogeneous group of rare disorders. Studies from large cohorts are essential to provide insights into the disease epidemiology, phenotypic spectrum, and mutational profiles. Here we enumerate additional 248 Indians from 197 families with a skeletal dysplasia, following a similar study earlier. We achieved a clinical-molecular diagnosis in 145 families by targeted analysis in 37 and next generation sequencing (exomes and genomes) in 108 families that resulted in a diagnostic yield of 73.6% (145 of 197 families). We identified 149 causal variants, of which 85 were novel, across 73 genes. Eighty-one distinct monogenic forms of skeletal dysplasia were observed with a high proportion of autosomal recessive skeletal dysplasias (60%, 84 families). We observed consanguinity in 35% of the families. Lysosomal storage diseases with skeletal involvement, FGFR3-related skeletal dysplasia and disorders of bone mineralisation were most frequent in this cohort. We expand the phenotypic and genotypic spectrum of rarely reported conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA, FUZand RSPRY1) and noted novel gene-disease relationships for PISD, BNIP1, TONSL, CCN2and SCUBE3related skeletal dysplasia. We successfully implemented genomic testing for skeletal dysplasia in clinical and research settings. Our study provides valuable information on the spectrum of skeletal dysplasia and disease-causing variants for Asian Indians.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder caused by impaired osteoclast activity. In this study, we describe a 4-year-old boy with increased bone density due to osteopetrosis, autosomal recessive 8. Using genome sequencing, we identified a large deletion in the 5′-untranslated region (UTR) of SNX10(sorting nexin 10), where the regulatory region of this gene is located. This large deletion resulted in the absence of the SNX10transcript and led to abnormal osteoclast activity. SNX10is one of the nine genes known to cause ARO, shown to interact with V-ATPase (vacuolar type H( + )-ATPase), as it plays an important role in bone resorption. Our study highlights the importance of regulatory regions in the 5′-UTR of SNX10for its expression while also demonstrating the importance of genome sequencing for detecting large deletion of the regulatory region of SNX10.

VAC14-related disorders include two distinct phenotypes, striatonigral degeneration [MIM# 617054] and Yunis–Varon syndrome. Striatonigral degeneration is a recently described childhood onset dystonia caused by pathogenic variants in VAC14. It is characterized by a period of apparent normalcy followed by abrupt onset neuroregression, dystonia, involuntary movements and degenerative brain lesions involving caudate nucleus, putamen and substantia nigra. Yunis–Varon syndrome is a well described severe condition characterised by skeletal findings and dysmorphism along with neuronal degeneration. Pathogenic variants in FIG4have been previously reported to cause Yunis–Varon syndrome. Recently, loss of function variants in VAC14were also reported in an individual affected with Yunis–Varon syndrome. Total seven individuals from four families are reported to have VAC14-related disorders till date. Here, we report another individual with clinical and radiological features suggestive of striatonigral degeneration with homozygous missense variant in VAC14. The patient fibroblasts showed extensive vacuolization, characteristic of VAC14-related disorders. We also review the phenotype and genotype associated with these disorders.

We report two brothers from a consanguineous couple with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones, probably representing a yet uncharacterized SEMD with laxity and dislocations. This condition has clinical overlap with autosomal dominantly inherited SEMD with joint laxity, leptodactylic type caused by recurrent missense variants in the kinesin family member 22 gene (KIF22). Single-nucleotide polymorphism array analysis and whole-exome sequencing in the two affected siblings revealed a shared homozygous nonsense variant [c.906T>A/p.(Tyr302*)] in EXOC6B as the most likely cause. EXOC6B encodes a component of the exocyst complex required for tethering secretory vesicles to the plasma membrane. As transport of vesicles from the golgi apparatus to the plasma membrane occurs through kinesin motor proteins along microtubule tracks, the function of EXOC6B is linked to KIF22 suggesting a common pathogenic mechanism in skeletal dysplasias with joint laxity and dislocations.