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The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.

Biallelic variants in RSPRY1 have been found to result in spondyloepimetaphyseal dysplasia. Two siblings presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, and short metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene. The phenotype in our patients resembles spondyloepimetaphyseal dysplasia, Faden‐Alkuraya type. Thus, our study provides further evidence to support the association of RSPRY1 variants with spondyloepimetaphyseal dysplasia. We observed joint dislocation as a novel clinical feature of this condition. [ABSTRACT FROM AUTHOR]

PRKACA‐related, atrial defects‐polydactyly‐multiple congenital malformation syndrome is a recently described skeletal ciliopathy, which is caused by disease‐causing variants in PRKACA. The primary phenotypic description includes atrial septal defects, and limb anomalies including polydactyly and short limbs. To date, only four molecularly proven patients have been reported in the literature with a recurrent variant, c.409G>A p.Gly137Arg in PRKACA. In this study, we report the fifth affected individual with the same variant and review the clinical features and radiographic findings of this rare syndrome. [ABSTRACT FROM AUTHOR]

Skeletal dysplasias (SKDs) are a heterogeneous group of more than 750 genetic disorders characterized by abnormal development, growth, and maintenance of bones or cartilage in the human skeleton. SKDs are often caused by variants in early patterning genes and in many cases part of multiple malformation syndromes and occur in combination with non‐skeletal phenotypes. The aim of this study was to investigate the underlying genetic cause of congenital SKDs in highly consanguineous Pakistani families, as well as in sporadic and familial SKD cases from India using multigene panel sequencing analysis. Therefore, we performed panel sequencing of 386 bone‐related genes in 7 highly consanguineous families from Pakistan and 27 cases from India affected with SKDs. In the highly consanguineous families, we were able to identify the underlying genetic cause in five out of seven families, resulting in a diagnostic yield of 71%. Whereas, in the sporadic and familial SKD cases, we identified 12 causative variants, corresponding to a diagnostic yield of 44%. The genetic heterogeneity in our cohorts was very high and we were able to detect various types of variants, including missense, nonsense, and frameshift variants, across multiple genes known to cause different types of SKDs. In conclusion, panel sequencing proved to be a highly effective way to decipher the genetic basis of SKDs in highly consanguineous families as well as sporadic and or familial cases from South Asia. Furthermore, our findings expand the allelic spectrum of skeletal dysplasias. [ABSTRACT FROM AUTHOR]

CHST3‐related chondrodysplasia with congenital joint dislocations (CDCJD, #MIM 143095), is a rare genetic skeletal disorder caused by biallelic loss of function variants in CHST3. CHST3 is critical for the sulfation of chondroitin sulfate. This study delineates the clinical presentation of nine individuals featuring the key symptoms of CDCJD; congenital joint (knee and elbow) dislocations, short trunk short stature progressive vertebral anomalies, and metacarpal shortening. Additional manifestations include irregular distal femoral epiphysis, supernumerary carpal ossification centers, bifid humerus, club foot, and cardiac abnormalities. Sanger sequencing was carried out to investigate molecular etiology in eight patients and exome sequencing in one. Genetic testing revealed five homozygous variants in CHST3 (four were novel and one was previously reported). All these variants are located on sulfotransferase domain of CHST3 protein and were classified as pathogenic/ likely pathogenic. We thus report on nine individuals with CHST3‐related chondrodysplasia with congenital joint dislocations from India and suggest monitoring the health of cardiac valves in this condition. [ABSTRACT FROM AUTHOR]

Background Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus. Methods Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents. Results 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously. Conclusion This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare 'Golgipathies'. [ABSTRACT FROM AUTHOR]

Background Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I--IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-Osulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described. Methods In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation- specific ARSK constructs derived by site- directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LCMS)/ MS analysis. Results The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK- specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS. Conclusion Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X [ABSTRACT FROM AUTHOR]

Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder caused by mutational inactivation of a developmental pathway responsible for generation of tissues of ectodermal origin. The X‐linked form accounts for the majority of HED cases and is caused by Ectodysplasin (EDA) pathogenic variants. We performed a combined analysis of 29 X‐linked hypohidrotic ectodermal dysplasia (XLHED) families (including 12 from our previous studies). In addition to the classical triad of symptoms including loss (or reduction) of ectodermal structures, such as hair, teeth, and sweat glands, we detected additional HED‐related clinical features including facial dysmorphism and hyperpigmentation in several patients. Interestingly, global developmental delay was identified as an unusual clinical symptom in many patients. More importantly, we identified 22 causal pathogenic variants that included 15 missense, four small in‐dels, and one nonsense, splice site, and large deletion each. Interestingly, we detected 12 unique (India‐specific) pathogenic variants. Of the 29 XLHED families analyzed, 11 (38%) harbored pathogenic variant localized to the furin cleavage site. A comparison with HGMD revealed significant differences in the frequency of missense pathogenic variants; involvement of specific exons and/or protein domains and transition/transversion ratios. A significantly higher proportion of missense pathogenic variants (33%) localized to the EDA furin cleavage when compared to HGMD (7%), of which p.R155C, p.R156C, and p.R156H were detected in three families each. Therefore, the first comprehensive analysis of XLHED from India has revealed several unique features including unusual clinical symptoms and high frequency of furin cleavage site pathogenic variants. [ABSTRACT FROM AUTHOR]

Bi‐allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley–Salih–Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants. [ABSTRACT FROM AUTHOR]

Spondyloepimetaphyseal dysplasias (SEMD) are a group of genetically heterogeneous skeletal disorders characterized by abnormal vertebral bodies and epimetaphyseal abnormalities. We investigated two families with a new SEMD type with one proband each. They showed mild facial dysmorphism, flat vertebral bodies (platyspondyly), large epiphyses, metaphyseal dysplasia, and hallux valgus as common clinical features. By trio‐exome sequencing, the homozygous missense variant c.797G>A/p.(Cys266Tyr) in PISD was found in both affected individuals. Based on exome data analyses for homozygous regions, the two patients shared a single homozygous block on chromosome 22 including PISD, indicating their remote consanguinity. PISD encodes phosphatidylserine (PS) decarboxylase that is localized in the inner mitochondrial membrane and catalyzes the decarboxylation of PS to phosphatidylethanolamine (PE) in mammalian cells. PE occurs at high abundance in mitochondrial membranes. Patient‐derived fibroblasts showed fragmented mitochondrial morphology. Treatment of patient cells with MG‐132 or staurosporine to induce activation of the intrinsic apoptosis pathway revealed significantly decreased cell viability with increased caspase‐3 and caspase‐7 activation. Remarkably, ethanolamine (Etn) supplementation largely restored cell viability and enhanced apoptosis in MG‐132‐stressed patient cells. Our data demonstrate that the biallelic hypomorphic PISD variant p.(Cys266Tyr) is associated with a novel SEMD form, which may be treatable with Etn administration. Trio exome sequencing in two different families with one child each with short stature, platyspondyly and large epiphyses revealed a shared homozygous missense variant c.797G>A/p.(Cys266Tyr) in PISD. Studies on patient‐derived fibroblasts confirmed the pathogenicity of this variant suggesting that the children have a new form of spondyloepimetaphyseal dysplasia. [ABSTRACT FROM AUTHOR]

Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous disorder. Although differential diagnosis is greatly facilitated by next generation sequencing, its availability can vary considerably. In this study, we compared targeted gene panel or exome sequencing with clinical scoring and grouping in a cohort of 50 OI index patients recruited by a single Indian clinical center in an unselected fashion. In 48 patients we observed a total of 24 novel mutations and 24 known OI mutations, of which several were recurrent. In one patient neither gene panel nor exome sequencing revealed any significant mutation and another patient harbored a class III COL1A1 intronic variant. The percentage of autosomal recessive forms due to mutations in BMP1 , FKBP10 , LEPRE1 , SERPINF1 , and WNT1 was unusually high (48%). Grouping according to phenotypic and radiographic features revealed four individuals with Bruck syndrome due to FKBP10 mutations, three patients with hypertrophic callus caused by IFITM5 mutations, and twenty with pronounced bone bowing, of which eight carried WNT1 mutations. There was a clear correlation between genotype and phenotype severity: IFITM5 = LEPRE1 > WNT1 > SERPINF1 > COL1A1 (qualitative) > BMP1 > FKBP10 > COL1A2 (qualitative) > COL1A1 (quantitative) > COL1A2 (quantitative). In one patient we found heterozygous variants in COL1A1 and COL1A2 inherited from parents without an obvious bone phenotype indicating that both variants might contribute to the phenotype. Our findings demonstrate the clinical utility of gene panel testing for OI, but in cases with contractures, hypertrophic callus formation, or – to some extent – extensive bowing single gene analysis might still be more cost-effective. [ABSTRACT FROM AUTHOR]

Acid sphingomyelinase (ASM)-deficient Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the SMPD1 gene. To date, around 185 mutations have been reported in patients with ASM-deficient NPD world-wide, but the mutation spectrum of this disease in India has not yet been reported. The aim of this study was to ascertain the mutation profile in Indian patients with ASM-deficient NPD. We sequenced SMPD1 in 60 unrelated families affected with ASM-deficient NPD. A total of 45 distinct pathogenic sequence variants were found, of which 14 were known and 31 were novel. The variants included 30 missense, 4 nonsense, and 9 frameshift (7 single base deletions and 2 single base insertions) mutations, 1 indel, and 1 intronic duplication. The pathogenicity of the novel mutations was inferred with the help of the mutation prediction software MutationTaster, SIFT, Polyphen-2, PROVEAN, and HANSA. The effects of the identified sequence variants on the protein structure were studied using the structure modeled with the help of the SWISS-MODEL workspace program. The p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population. To the best of our knowledge, this is the largest study on mutation analysis of patients with ASM-deficient Niemann-Pick disease reported in literature and also the first study on the SMPD1 gene mutation spectrum in India. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia characterized by progressive osteolysis and arthropathy. Inactivating mutations in MMP2, encoding matrix metalloproteinase-2, are known to cause this disorder. Fifteen families with mutations in MMP2 have been reported in literature. In this study we screened thirteen individuals from eleven families for MMP2 mutations and identified eight mutations (five novel and three known variants). We characterize the clinical, radiographic and molecular findings in all individuals with molecularly proven MONA from the present cohort and previous reports, and provide a comprehensive review of the MMP2 related disorders. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The cover image, by Katta M. Girisha et al., is based on the Original Article Additional three patients with smithmccort dysplasia due to novel rab33b mutations, DOI: 10.1002/ajmg.a.38064. [ABSTRACT FROM AUTHOR]

Abstract Genetic heterogeneity, high burden and the paucity of genetic testing for rare diseases challenge genomic healthcare for these disorders in India. Here we report our experience over the past decade, of establishing the genomic evaluation of skeletal dysplasia at a tertiary university hospital in India. Research or clinical genomic testing was carried out by Sanger sequencing and next-generation sequencing. Close national and international collaborations aided phenotyping and genotyping. We report 508 families (557 affected individuals) with the definitive molecular diagnosis of skeletal dysplasia. Dysostoses multiplex (n = 196), genetic inflammatory/rheumatoid-like osteoarthropathies (n = 114) and osteogenesis imperfecta and decreased bone density (n = 58) were the most common diagnoses. We enumerate the processes, clinical diagnoses and causal variants in the cohort with 48 novel variants in 21 genes. We summarize scientific contributions of the center to the description of clinical and mutation profiles and discovery of new phenotypes and genetic etiology. Our study illustrates the establishment and application of genomic testing tools for genetic disorders of skeleton in a large cohort. We believe this could be a model to emulate for other developing genetic centers. Graphical abstract Unlabelled Image Highlights • We enumerate 557 individuals from 508 families with definitive molecular diagnosis of a skeletal dysplasia • The work adds 48 previously unreported variants in 21 genes as the likely cause of a skeletal dysplasia to the literature • The paper illustrates establishment and application of genomic testing tools for skeletal dysplasias in a large cohort [ABSTRACT FROM AUTHOR]

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.