Search

Background: Our objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation. Methods: We recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <−1 standard deviation. The genotype-phenotype correlation was studied. Results: Four children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as 'disease causing', and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop. Conclusions: Pathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS. [ABSTRACT FROM AUTHOR]

Purpose: Leber's hereditary optic neuropathy (LHON) is an inherited optic neuropathy characterized by subacute painless vision loss. The majority of LHON is caused due to one of the three primary mutations in the mitochondrial DNA (m.G3460A, m.G11778A, and m.T14484C). The frequency of these mutations differs in different populations. The purpose of this study is to observe the frequency of three common primary mutations in the North Indian population.Methods: Forty LHON patients within the age group of 10-50 years underwent molecular testing for primary mutations. For two patients, testing for mother and other siblings was also carried out, using bidirectional sequencing.Results: A total of 11 out of 40 (27.5%) patients were found to be carrying m.G11778A mutation. Siblings of two probands were also positive for the same mutation. In one family, two primary mutations (m.G11778A and m.T14484C) were found in the proband and in the mother as well.Conclusion: In this study, 27.5% mutation was detected in North Indian LHON families. These results suggest that m.G11778A mutation is more frequent in this population. The results of the present study are compatible with studies of an Asian population and Northern European population. [ABSTRACT FROM AUTHOR]

Molecular genetic testing for fragile X (FX) is complicated due to the large variation in the size of CGG expansion. The aim of this study was to apply this new technique using AmplideX FMR1 PCR assay, which is considered a better diagnostic tool for detecting expanded alleles in Indian population. The primary objective was to identify the carrier status of females and to correlate the instability of premutation alleles in females with the repeat sizes. 24 children with FX based on rapid PCR and 29 female relatives of these patients were included. Out of the 29 females screened, those whose child (or children) was affected by FX, were all premutation carriers confirming their role in transmission. The smallest PM allele that expanded into FM in the next generation was 78 repeats and the smallest PM allele detected was 63 repeats, and when transmitted from mother to offspring remained in the premutation range. In 4 families, the repeat size of the allele reduced from PM to normal repeat numbers in their daughters and in 1 case to borderline PM range. Thus, apart from the reduced turnaround time, this PCR based assay offers advantage by its sensitivity to detect CGG repeats in the intermediate region and lower range of premutation alleles. It also provides added information of AGG interruptions, which may have an impact on the counseling of women with intermediate and PM alleles. [ABSTRACT FROM AUTHOR]

The present study was designed as a 12-week, randomized, double-blind, placebo-controlled pilot study to evaluate the effectiveness and safety of donepezil in boys with fragile X syndrome. Twenty boys with fragile X syndrome were randomized to receive 12 weeks of treatment with either placebo or donepezil (2.5 mg daily for initial 4 weeks followed by 5 mg daily for next 8 weeks). The outcome measures included change in intelligence quotient scores on Stanford-Binet Intelligence Scale (Hindi adaptation by Kulshrestha), change in behavioral scores by Conners 3 Parent Rating Scale (Short) and Childhood Autism Rating Scale, safety, and tolerability of donepezil. The study failed to show significant difference in intelligence quotient and behavioral scales with donepezil therapy over 12 weeks. However, donepezil appeared to be safe and well tolerated. [ABSTRACT FROM AUTHOR]

Background & objectives: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder with a wide range of clinical manifestations. The disease is attributed to mutations in CYP21A2 gene encoding 21-hydroxylase enzyme. In view of severe phenotype in salt-losing cases, issues related to genital ambiguity in girls and precocity in boys, most families opt for prenatal testing and termination of affected foetus. CAH can be diagnosed in utero through direct molecular analysis of CYP21A2 gene, using DNA extracted from foetal tissues or cells obtained from chorionic villus sampling or amniocentesis. The objective of this study was to evaluate the feasibility and accuracy of prenatal diagnosis (PND) using sequencing and multiplex ligation probe amplification (MLPA) methods in families at risk for CAH. Methods: Fifteen pregnant women at risk of having an affected offspring with CAH were included in this study. Ten families had previous affected children with salt-wasting/simple virilising form of CAH and five families did not have live children but had a high index of suspicion for CAH in previous children based on history or records. Mutation analysis was carried out by Sanger sequencing and MLPA method. Results: Seven different mutations were identified in 15 families. Deletions and I2g mutation were the most common. Of the 15 foetuses analyzed, nine were unaffected while six were affected. Unaffected foetuses were delivered, they were clinically normal and their genotype was found to be concordant to the prenatal report. All except two families reported in the second trimester. None of the couples opted for prenatal treatment. Interpretation & conclusions: Our preliminary findings show that PND by direct mutation analysis along with MLPA is a feasible strategy that can be offered to families at risk. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID)/Global developmental delay (GDD) is a diverse group of disorders in terms of cognitive and non-cognitive functions and can occur with or without associated co-morbidities. It affects 1–3% of individuals globally and in at least 30–50% of cases the etiology remains unexplained. The widespread use of chromosomal microarray analysis (CMA) in a clinical setting has allowed the identification of submicroscopic copy number variations (CNVs), throughout the genome, associated with neurodevelopmental phenotypes including ID/GDD. In this study we investigated the utility of CMA in the detection of CNVs in 106 patients with unexplained ID/DD, dysmorphism with or without multiple congenital anomalies (MCA). CMA study was carried out using Agilent 8 × 60 K chips and Illumina Human CytoSNP-12 chips. Pathogenic CNVs were found in 15 (14.2%) patients. In these patients, CNVs on single chromosome were detected in 10 patients while 5 patients showed co-occurrence CNVs on two chromosomes. The size of these CNVs ranged between 322 kb to 13 Mb. The yield of pathogenic CNVs was similar for both mild and severe ID/GDD cases. One patient described in this paper is considered to harbour a likely pathogenic CNV with deletion in 17q22 region. Only few cases have been described in literature for 17q22 deletion and patient reported here was found to have an atypical deletion in 17q22 region (Case 90). This study re-affirms the view point that CMA is a powerful diagnostic tool in the evaluation of idiopathic ID/GDD patients irrespective of the degree of severity. Identifying pathogenic CNVs helps in counseling and prenatal diagnosis if desired. [ABSTRACT FROM AUTHOR]

Background & objectives: Hearing impairment is a common and heterogeneous sensory disorder in humans. Among about 90 genes, which are known to be associated with hearing impairment, mutations in the GJB2 (gap junction protein beta 2) gene are the most prevalent in individuals with hereditary hearing loss. Contribution of the other deafness-causing genes is relatively poorly understood. Here, we present our findings on two families with transmembrane channel like 1 (TMC1) gene variants of the 47 families with nonsyndromic hearing loss (NSHL) studied. Methods: Forty seven families including 26 consanguineous families with at least two hearing impaired children and one normal hearing child and 21 non-consanguineous families having at least three hearing impaired children and one normal hearing child were enrolled for this study. Genetic linkage studies were carried out in 41 families that were GJB2 (Connexin 26) negative. Seven polymorphic short tandem repeat markers at the DFNB7/11 locus were studied employing fluorescently labelled markers. Results: A novel homozygous missense mutation c.1283C>A (p.Ala428Asp) was identified co-segregating with hearing loss. This change results in substitution of a highly conserved polar alanine to a charged aspartic acid and is predicted to be deleterious. In addition, a previously reported nonsense mutation, p.R34X in TMC1, was found. Interpretation & conclusions: While mutations in TMC1 are not as common a cause of NSHL as those in GJB2, TMC1 should be considered for diagnostic investigations in cases of NSHL in GJB2-negative families. [ABSTRACT FROM AUTHOR]