Gandham SriLakshmi Bhavani

A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy

Intraflagellar transport (IFT) is vital for the functioning of primary cilia. Defects in several components of IFT complexes cause a spectrum of ciliopathies with variable involvement of skeleton, brain, eyes, ectoderm and kidneys. We examined a child from a consanguineous family who had short stature, narrow thorax, short hands and feet, postaxial polydactyly of hands, pigmentary retinopathy, small teeth and skeletal dysplasia. The clinical phenotype of the child shows significant overlap with cranioectodermal dysplasia type I (Sensenbrenner syndrome). Whole‐exome sequencing revealed a homozygous nonsense variant p.R142* in IFT52 encoding an IFT‐B core complex protein as the probable cause of her condition. This is the first report of a human disease associated with IFT52.

Progressive Pseudorheumatoid Dysplasia

Abstract. A rare case of progressive pseudorheumatoid dysplasia (PPD) in a 9-year-old girl is presented. Clinically, chronic painless swollen joints, accompanied by progressive motion restriction and progressive walking difficulties, were found. Radiologically, there was enlargement of the epimetaphyseal portions of the large joints, metacarpal heads, and phalanges, and generalized platyspondyly with irregular delineation of the endplates of the vertebral bodies. The radioclinical features at the peripheral joints were originally misdiagnosed as juvenile rheumatoid arthritis (JRA), and the structural spinal abnormalities were neglected and interpreted as Scheuermanns disease. However, the absence of active inflammatory parameters argues against JRA, whereas the low age of onset of the irregularities at the vertebral endplates is an argument against the diagnosis of Scheuermanns disease. The combination of the dysplastic abnormalities of the spine, with platyspondyly and Scheuermann-like lesions at an unusually low age of onset, and radiological features mimicking JRA of the peripheral joints, is the clue to the diagnosis of this rare autosomal-recessive disease. This case is the first to document the MRI features of PPD of the spine.

The promise of discovering population-specific disease-associated genes in South Asia

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 identify 81 unique groups, of which 14 have estimated census sizes of more than a 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 identify multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an under-appreciated opportunity for reducing disease burden among South Asians through the discovery of and testing for recessive disease genes.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.

Novel and recurrent mutations in WISP3 and an atypical phenotype

Novel and Recurrent Mutations in WISP3 and an Atypical Phenotype Gandham SriLakshmi Bhavani, Hitesh Shah, Ashwin B. Dalal, Anju Shukla, Sumita Danda, Shagun Aggarwal, Shubha R. Phadke, Neerja Gupta, Madhulika Kabra, Kalpana Gowrishankar, Anju Gupta, Meenakshi Bhat, Ratna D. Puri, Sunita Bijarnia-Mahay, Sheela Nampoothiri, Kavitha M. Mohanasundaram, S. Rajeswari, Akhil M. Kulkarni, Muralidhar L. Kulkarni, Prajnya Ranganath, A. Radha Ramadevi, Sankar V. Hariharan, and Katta Mohan Girisha* Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India Department of Orthopedics, Pediatric Orthopedics Services, Kasturba Medical College, Manipal University, Manipal, India Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, India Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, India Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Department of Pediatrics, Division of Genetics, All India Institute of Medical Science, New Delhi, India Department of Medical Genetics, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India Centre for Human Genetics, Bangalore, India Centre of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Ponekkara, Cochin, Kerala, India Department of Rheumatology, Madras Medical College, Chennai, India Department of Radiodiagnosis, SS Institute of Medical Sciences and Research Centre, Davangere, India Department of Pediatrics, Jagadguru Jayadeva Murugarajendra Medical College, Davangere, India Department of Clinical Genetics, Genetics Unit, Rainbow Children Hospital, Hyderabad, India Department of Pediatrics, Sree Avittom Thirunal Hospital, Government Medical College, Trivandrum, India

Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy.

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.

Additional Three Patients With Smith-McCort Dysplasia Due to Novel RAB33B Mutations

Smith‐McCort dysplasia (SMC OMIM 615222) and Dyggve‐Melchior‐Clausen dysplasia (DMC OMIM 223800) are allelic skeletal dysplasias caused by homozygous or compound heterozygous mutations in DYM (OMIM 607461). Both disorders share the same skeletal phenotypes characterized by spondylo‐epi‐metaphyseal dysplasia with distinctive lacy ilia. The difference rests on the presence or absence of intellectual disability, that is, intellectual disability in DMC and normal cognition in SMC. However, genetic heterogeneity was suspected in SMC. Recently, RAB33B (OMIM 605950) has been identified as the second gene for SMC. Nevertheless, only two affected families have been reported so far. Here we present three SMC patients with four novel pathogenic variants in RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*). We also summarize the clinical, radiological, and mutation profile of RAB33B after literature mining. This report ascertains the pathogenic relationship between RAB33B and SMC.

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene

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.

A syndrome of facial dysmorphism, cubital pterygium, short distal phalanges, swan neck deformity of fingers, and scoliosis

We report on an adolescent girl with sparse scalp hair, wide columella extending below alae nasi, webbing at elbows, broad finger tips, short distal phalanx of fingers, swan neck deformity of fingers, scoliosis, tall vertebrae, short fibulae, short fourth metatarsal bone, abnormal distal humeri, and unilateral clubfoot at birth. The combination of these features represents a novel phenotype. We sequenced the protein‐coding regions of the FLNA and FLNB genes and did not observe any pathogenic sequence variation. Chromosomal microarray revealed a de novo copy number variation of uncertain clinical significance on 7p22.3.

Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta.

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.

Spectrum of mutations in the SMPD1 gene in Asian Indian patients with acid sphingomyelinase deficient Niemann-Pick disease

Prajnya Ranganath, Divya Matta, Gandham SriLakshmi Bhavani, Savita Wangnekar, Jamal Mohammed Nurul Jain, Ishwar C. Verma, Madhulika Kabra, Ratna D. Puri, Sumita Danda, Neerja Gupta, Katta M. Girisha, Vaikom H. Sankar, Siddaramappa J. Patil, Akella Radha Rama Devi, Meenakshi Bhat, Kalpana Gowrishankar, Kausik Mandal, Shagun Aggarwal, Parag Mohan Tamhankar, Preetha Tilak, Shubha R. Phadke, and Ashwin Dalal