Kausik Mandal

Use of Multiplex Ligation-Dependent Probe Amplification (MLPA) in screening of subtelomeric regions in children with idiopathic mental retardation

ObjectiveTo detect subtelomeric copy number variations (deletions and duplications) using Multiplex Ligation-Dependent Probe Amplification (MLPA) technique in children with idiopathic mental retardation.MethodsAll children presenting to the genetics out-patient department for evaluation of mental retardation or developmental delay over a period of two years, for whom no identifiable cause could be found by clinical evaluation, karyotyping, neuroimaging and other relevant investigations.ResultsIn the present study, two cases deletions and one case of duplication were detected amongst 65 cases with idiopathic mental retardation/ global developmental delay. The overall detection rate is 4.6%. The detection rate is higher (13%) in children with facial dysmorphism.ConclusionMLPA for subtelomeric regions is recommended for evaluation of children with idiopathic mental retardation/ global developmental delay were included in the study.

Noonan syndrome in diverse populations

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low‐set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.

Novel mutations in the transmembrane natriuretic peptide receptor NPR-B gene in four Indian families with acromesomelic dysplasia, type Maroteaux

Acromesomelic dysplasia, type Maroteaux is a disorder characterized by disproportionate short stature predominantly affecting the middle and distal segments of the upper and lower limbs. It is an autosomal recessive disorder due to mutation in NPR2 gene which impairs skeletal growth. To screen the mutations in the gene NPR2, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected individuals of four families and sequenced. Four homozygous mutations in four different families were identified. These include three novel mutations including a deletion frameshift mutation (p.Cys586Ter), one nonsense mutation (p.Arg479Ter), one missense mutation (p.Val187Asp) and one reported missense mutation (p.Tyr338Cys). The study describes phenotypes of Indian patients and expands the mutation spectrum of the disorder.

Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with mucopolysaccharidoses type I and type II.

Mucopolysaccharidoses (MPS), a subgroup of lysosomal storage disorders, are caused due to deficiency of specific lysosomal enzyme involved in catabolism of glycosaminoglycans. To date more than 200 pathogenic variants in the alpha‐l‐iduronidase (IDUA) for MPS I and ∼500 pathogenic variants in the iduronate‐2‐sulphatase (IDS) for MPS II have been reported worldwide. The mutation spectrum of MPS type I and MPS type II disorders in Indian population is not characterized yet. In this study, we carried out clinical, biochemical, molecular and in silico analyses to establish the mutation spectrum of MPS I and MPS II in the Indian population. We conducted molecular analysis for 60 MPS‐affected patients [MPS I (n = 30) (Hurler syndrome = 17, Hurler–Scheie syndrome = 13), and MPS II (n = 30) (severe = 18, attenuated = 12)] and identified a total of 44 [MPS I (n = 22) and MPS II (n = 22)] different pathogenic variants comprising missense, nonsense, frameshift, gross deletions and splice site variants. A total of 20 [MPS I (n = 14), and MPS II (n = 6)] novel pathogenic sequence variants were identified in our patient cohort. We found that 32% of pathogenic variants detected in IDUA were recurrent and 25% in MPS II. This is the first study revealing the mutation spectrum of MPS I and MPS II patients in the Indian population.

Milder form of pachydermoperiostosis: a report of four cases.

Pachydermoperiostosis is known to occur in three distinct forms: complete, incomplete, and form fruste. We report four patients with clubbing and a cylindrical appearance of lower legs without pachydermia and periostosis. We believe that this represents a milder, but distinct subgroup of pachydermoperiostosis. One family showed probable autosomal recessive inheritance.

Smith-Magenis Syndrome: Face Speaks

Smith-Magenis syndrome is a well delineated microdeletion syndrome with characteristic facial and behavioral phenotype. With the availability of the multi-targeted molecular cytogenetic techniques like Multiplex Ligation Probe Amplification and cytogenetic microarray, the cases are diagnosed even without clinical suspicion. Here, the authors present clinical features of nine Indian cases of Smith-Magenis syndrome. Characteristic facial phenotype including tented upper lip, broad forehead, midface hypoplasia, short philtrum and upslant of palpebral fissure is obvious in the photographs. The behavioral variations were seen in some of the cases but were not the presenting features. The characteristic facial phenotype can be an important clinical guide to the diagnosis.

Pycnodysostosis: mutation spectrum in five unrelated Indian children.

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad and Department of Pediatrics, Genetics Division, All India Institute of Medical Sciences, New Delhi, India Correspondence to Kausik Mandal, MD, DM, Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibereli Road, Lucknow 226014, India Tel: + 91 522 249 4327/+ 91 740 872 5914; fax: + 91 522 266 8017; e-mail: mandal.kausik@gmail.com

Familial 18p deletion syndrome and 18p partial trisomy inherited from a mother with balanced translocation.

18p deletion syndrome can be easily missed in a clinical setting as the facial features, though typical, can be overlooked and the other features including growth retardation and learning disability are nonspecific. We present a family in which the proband has 18p deletion syndrome. The proband performed better on verbal skills than on performance tasks on intelligence testing. She had attention-deficit hyperactivity disorder, which required medication and behavioral therapy. Subsequent cytogenetic analysis in her elder brother who presented with learning difficulties showed partial trisomy 18p and the maternal karyotype is 46, XX,(15;18)(p11.2;p11.2). This is the first report of a family with a balanced maternal translocation resulting in 18p deletion in one sibling and 18p partial trisomy in the other.

Congenital swan neck deformity of fingers with syndactyly.

Congenital swan neck deformity of the fingers is an uncommon congenital disorder. It is sporadic and not associated with other malformations. We report a case of congenital swan neck deformity of the fingers in a 16-year-old boy, with associated ulnar deviation of the fingers, bilateral simian creases and soft tissue syndactyly.

Spondyloepiphyseal dysplasia Omani type: CHST3 mutation spectrum and phenotypes in three Indian families

We describe three consanguineous Indian families with a distinct form of spondyloepiphyseal dysplasia (SED Omani type). It is an autosomal recessive disorder due to mutation in CHST3 gene. CHST3 gene encodes the enzyme chondroitin 6‐O‐sulfotransferase‐1 (C6ST‐1) which mediates the sulfation of proteoglycans, (chondroitin sulfate), in the extracellular matrix of cartilage. CHST3 gene was sequenced in probands from three different families with SED. In two families missense mutations (c.904G>C predicting the substitution D302H) and c.491C>T (P164L) were identified. A frameshift (insertion) mutation (c.533_534ins G predicting the substitution A179Rfs*) was found in the third family. SNP micrarray in the family 2 helped to localize the common areas of homozygosity and identified the candidate gene. The confirmation by molecular diagnosis will be useful in the management and in the counseling of affected patients and their families. The presence of sclerosis of cranial sutures adds to the phenotypic spectrum of the disorder. Severe cardiac valvular disease in a case and triangular epiphyses of knees are other features which are highlighted in this report.