Background: Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation. Methods: Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced. Results: Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%). Conclusion: The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

Glycogen storage disorders occur due to enzyme deficiencies in the glycogenolysis and gluconeogenesis pathway, encoded by 26 genes. GSD’s present with overlapping phenotypes with variable severity. In this series, 57 individuals were molecularly confirmed for 7 GSD subtypes and their demographic data, clinical profiles and genotype-phenotype co-relations are studied. Genomic DNA from venous blood samples was isolated from clinically affected individuals. Targeted gene panel sequencing covering 23 genes and Sanger sequencing were employed. Various bioinformatic tools were used to predict pathogenicity for new variations. Close parental consanguinity was seen in 76%. Forty-nine pathogenic variations were detected of which 27 were novel. Variations were spread across GSDIa, Ib, III, VI, IXa, b and c. The largest subgroup was GSDIII in 28 individuals with 24 variations (12 novel) in AGL. The 1620+1G>C intronic variation was observed in 5 with GSDVI (PYGL). A total of eleven GSDIX are described with the first Indian report of type IXb. This is the largest study of GSDs from India. High levels of consanguinity in the local population and employment of targeted sequencing panels accounted for the range of GSDs reported here.

BackgroundDyggve-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.MethodsDetailed 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.Results24 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.ConclusionThis large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare ‘Golgipathies’.