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Reshma Pandit, Kranti Khadilkar, Vijaya Sarathi, Rajeev Kasaliwal, Manjunath Goroshi, Shruti Khare, Sandhya Nair, Vijaya Raghavan, Abhay Dalvi, Priya Hira, Gwendolyn Fernandes, Pragati Sathe, Amey Rojekar, Gaurav Malhotra, Ganesh Bakshi, Gagan Prakash, Anil Bhansali, Rama Walia, Sadishkumar Kamalanathan, Jayaprakash Sahoo, Ankush Desai, Nikhil Bhagwat, Prashanth Mappa, Rajesh Rajput, Sudha Rao Chandrashekhar, Vyankatesh Shivane, Padma Menon, Anurag Lila, Tushar Bandgar and Nalin Shah

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Reshma Pandit, Kranti Khadilkar, Vijaya Sarathi, Rajeev Kasaliwal, Manjunath Goroshi, Shruti Khare, Sandhya Nair, Vijaya Raghavan, Abhay Dalvi, Priya Hira, Gwendolyn Fernandes, Pragati Sathe, Amey Rojekar, Gaurav Malhotra, Ganesh Bakshi, Gagan Prakash, Anil Bhansali, Rama Walia, Sadishkumar Kamalanathan, Jayaprakash Sahoo, Ankush Desai, Nikhil Bhagwat, Prashanth Mappa, Rajesh Rajput, Sudha Rao Chandrashekhar, Vyankatesh Shivane, Padma Menon, Anurag Lila, Tushar Bandgar and Nalini Shah

Background

Genetic aetiology of pheochromocytoma (PCC) and paraganglioma (PGL) is increasingly being studied; however, Asian Indian data on this aspect are scarce.

Objective

To study the prevalence of germline mutations and genotype–phenotype correlation in Asian Indian PCC/PGL patients.

Design

In this study, 150 index patients (M:F, 73:77) with PCC/PGL were evaluated. Phenotypic data were collected. Germline mutations in five susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) were tested by sequencing and NF1 was diagnosed according to phenotype.

Result

Of the total population, 49 (32.7%) PCC/PGL patients had germline mutations (VHL: 23 (15.3%), RET: 13 (8.7%), SDHB: 9 (6%), SDHD: 2 (1.3%) and NF1: 2 (1.3%)). Amongst the 30 patients with familial and/or syndromic presentation, all had germline mutations (VHL: 14 (46.7%), RET: 13 (43.3%), SDHB: 1 (3.3%) and NF1: 2 (6.7%)). Out of 120 patients with apparently sporadic presentation, 19 (15.8%) had a germline mutation (VHL: 9 (7.5%), SDHB: 8 (6.7%) and SDHD: 2 (1.7%)). Mutation carriers were younger (29.9 ± 14.5 years vs 36.8 ± 14.9; P = 0.01) and had a higher prevalence of bilateral PCC (26.5% vs 2.9%, P < 0.001) and multifocal tumours (12.2% vs 0.96%, P = 0.06). Based on syndromic features, metastasis, location and number of tumours, around 96% mutations in our cohort could be detected by appropriately selected single gene testing.

Conclusion

Asian Indians with PCC/PGL differ from Western cohorts in having preponderance of VHL mutations in multifocal tumours and apparently sporadic unilateral PCC. Syndromic presentation, metastasis, location and number of PCC/PGL can be effectively used for guiding genetic prioritisation.

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Sneha Arya, Ankita Tiwari, Anurag Ranjan Lila, Vijaya Sarathi, Vishwambhar Vishnu Bhandare, Bajarang Vasant Kumbhar, Khushnandan Rai, Ambarish Kunwar, Hemangini Thakkar, Kunal Thakkar, Saba Samad Memon, Virendra Patil, Kranti Khadilkar, Swati S Jadhav, Nalini S Shah and Tushar Bandgar

Objective:

To evaluate the pathogenic role of a few benign variants and hypomorphic pathogenic variants in SRD5A2.

Design and methods:

We retrospectively analyzed phenotypes and genotypes in 23 Indian patients with genetically proven steroid 5α-reductase 2 (SRD5A2) deficiency. The interactions of the SRD5A2 enzymes resulting due to the most common benign variant (p.Val89Leu), the most common (hypomorphic) pathogenic variant (p.Arg246Gln) and the double variants (p.Val89Leu and p.Arg246Gln) in SRD5A2 were compared with that of the wild type (WT) enzyme by molecular dynamics (MD) simulation.

Results:

The majority (n = 19, 82.61%) of patients presented for atypical genitalia and had male gender identity (16/20). Including the two novel ones (p.Leu83Pro, p.Ala28Leufs*103), a total of nine different pathogenic variants were observed. p.Arg246Gln was the most common pathogenic variant (n = 12). Homozygous p.Arg246Gln (n = 9) variant was associated with milder undervirilization (Sinnecker score of ≤3a: 8/9 vs 6/14, P = 0.04) and had concurrent homozygous p.Val89Leu in all patients. Interestingly, asymptomatic fathers of two index patients were homozygous for p.Arg246Gln which questioned the pathogenicity of the variation as a sole factor. Unlike all symptomatic homozygous p.Arg246Gln patients who were also homozygous for p.Val89Leu, asymptomatic homozygous p.Arg246Gln fathers were heterozygous for p.Val89Leu. On MD simulation SRD5A2 p.Val89Leu-Testeosterone (T) and SRD5A2 p.Arg246Gln-T complexes, but not SRD5A2 p.Val89Leu and p.Arg246Gln-T complex, demonstrated close interaction between NADPH and T as that of SRD5A2 WT-T.

Conclusions:

p.Arg246Gln may not be pathogenic as a sole variation even in the homozygous state; additional contribution of homozygous p.Val89Leu variant may be essential for the pathogenicity of p.Arg246Gln in SRD5A2.