Shagun Aggarwal

Skeletal dysplasias with increased bone density: evolution of molecular pathogenesis in the last century.

Skeletal dysplasias (SKD) with increased bone density form a discrete group of SKDs as per the Nosology and Classification of Genetic Skeletal Disorders, 2010 Revision. This group, with the prototype disorder being osteopetrosis, has evolved over the last century, with new entities being described & their molecular basis being increasingly elucidated. Osteopetrosis, which remained an enigma in the early part of its description, is now known to be genetically heterogenous. Other disorders in this group, which were initially described as variant forms of osteopetrosis, are now recognised to be distinct conditions. However, all these SKDs with increased bone density share their molecular pathogenesis as majority arise due to mutations in the genes governing osteoclast formation and function.

Recurrence of urorectal septum malformation sequence spectrum anomalies in siblings: time to explore the genetics.

Urorectal septum malformation sequence (URSM) is a pattern of malformation which encompasses abnormalities of the perineal orifices, external genitalia, genitourinary system, and anorectum. The spectrum ranges from a complete form with absence of perineal openings and persistent cloaca to milder/partial forms usually with one perineal opening and internal abnormalities of anorectum, urethra, and Müllerian structures. URSM is felt to arise due to abnormalities of the caudal mesoderm, which constitutes the urorectal septum. Here, we report two male siblings, affected with a spectrum of anomalies simulating URSM. This is the first report of recurrence of URSM in sibs. It suggests the existence of hitherto unknown genetic mechanisms for this pattern of malformation.

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

A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum.

We report on a sib pair of Indian origin presenting with intellectual disability, dysmorphism, and macrocephaly. Exome sequencing revealed a homozygous splice site HERC1 mutation in both probands. Functional analysis revealed use of an alternate splice site resulting in formation of a downstream stop codon and nonsense mediated decay. In the light of recent reports of HERC1 mutations in two families with a similar phenotypic presentation, this report reiterates the pathogenic nature and clinical consequences of HERC1 disruption.

Recurrent and novel GLB1 mutations in India.

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme β-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, β-domain 1 and β-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India.

Intracardiac echogenic focus and fetal outcome

To study the outcome of the fetuses with intracardiac echogenic focus (ICEF).

Renal dysfunction in sibs with band like calcification with simplified gyration and polymicrogyria: Report of a new mutation and review of literature

Band like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a distinct neuroradiological phenotype initially reported as a pseudo-TORCH syndrome and known to result from biallelic mutations in the Occludin(OCLN) gene. This is report of a family of Indian origin with two affected sibs and segregation of a homozygous novel OCLN mutation in the exon 3(NG_028291.1(OCLN_v001):c.252delC). A literature review suggests that renal dysfunction may be an unrecognized phenotypic manifestation of OCLN mutations and monitoring for the same should form part of the clinical care of these individuals.

Medical genetics and genomic medicine in India: current status and opportunities ahead.

India is the sixth largest country of the world in size and with a population 1.21 billion (http://www.censusindia.gov.in) has the distinction of being the second most populous country of the world, housing 17.5% of all humans (http://www.prb.org). It is part of the Indian subcontinent that is comprised of the surrounding countries of Pakistan, Bangladesh, Srilanka, Nepal, and China with whom it shares common cultural and anthropological roots. The southern part of India is the Indian peninsula surrounded by the Indian Ocean, the Bay of Bengal, and the Arabian Sea (Fig. 1). The Indian subcontinent has been the seat of some of the oldest civilizations of the world with the earliest historically documented remains dating back to as early as 70,000 years. This region is believed to have been initially habituated 55,000– 80,000 years back by migration from the African continent as indicated by mitochondrial and Y chromosome DNA genotypes (Majumdar 2010; Tamang et al. 2012). Subsequently, multiple events of migration and invasions from northwestern and eastern sides led to population admixture giving rise to highly heterogeneous population groups in this country. Presently, there are believed to be four main ethno-racial groupsthe Caucasoids, Australoids, Mongoloids, and Negritosin India. The Caucasoids inhabit the northern and northwestern part and speak the Indo-Aryan langauages, the Australoids the southern part and speak the Dravidian languages and the Mongoloids the northeastern part of the country and speak the Tibeto-Burman languages. The Negritos are confined to the Andaman & Nicobar islands which lie in the extreme southeastern part of the country. The majority of the modern Indian population is an admixture of two large genetically divergent and heterogeneous population groups that mixed in ancient times (about 1200– 3500 BC), known as Ancestral North Indians (ANI) or the Caucasoids and Ancestral South Indians (ASI) or the Australoids. Overall there are more than 4000 anthropologically distinct groups and 22 languages with various dialects in this diverse nation (Majumdar 2010; Narang et al. 2010; Tamang et al. 2012). Genetic studies for classifying the population into subgroups and identifying the origins have been at the best incomplete due to the vast population and extreme complexity. This poses challenges for genetics and genomic medicine research. In recent years, the Indian Genome variation consortium project has studied polymorphisms in 900 genes from 55 different population groups of India and these variations have been catalogued in the Indian Genome Variation browser. This forms an important database for design of further studies of multifactorial as well as single gene disorders (Narang et al. 2010). The geographical & linguistic disparity is further complicated by the caste system and religious boundaries, which are associated with high degree of endogamy, although recent reports have indicated some degree of admixture (Tripathi et al. 2008; Majumdar 2010; Tamang et al. 2012; Juyal et al. 2014). Consanguinity is as high as 20–30% in some specific populations, indicating the possibility of clusters of specific diseases and founder mutations (Bittles 2002; Juyal et al. 2014). Although almost all known genetic disorders

A Novel Glycine Decarboxylase Gene Mutation in an Indian Family With Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is an inborn error of glycine metabolism. It manifests mostly as an acute encephalopathy in the neonatal period, although later, atypical presentations have also been reported. Mutations in 3 different genes have been implicated in nonketotic hyperglycinemia. Here we report a novel mutation, c.2296G>T (p.Gly766Cys), in exon 19 of the glycine decarboxylase (GLDC) gene (Refseq accession number NM_000170.2) in a consanguineous Indian couple with a history of 4 neonatal deaths.

Prenatal skeletal dysplasia phenotype in severe MLII alpha/beta with novel GNPTAB mutation

We report a neonate who was diagnosed as a case of skeletal dysplasia during pregnancy, and was subsequently diagnosed as a case of MLII alpha/beta on the basis of clinical and radiological findings and molecular testing of the parents. A novel GNPTAB mutation c.1701delC [p.F566LfsX5] was identified in the father. The case reiterates the severe prenatal phenotype of MLII alpha/beta which mimics skeletal dysplasia and illustrates the utility of molecular genetic analysis in confirmation of diagnosis and subsequent genetic counselling.