Neetu Singh1, Devendra Kumar Gupta2, Shilpa Sharma3, Dinesh Kumar Sahu4, Archana Mishra4, Devendra Kumar Yadav3, Jiledar Rawat5, Arun Kumar Singh6. 1. Molecular Biology Unit (Center for Advance Research), King George's Medical University, Lucknow, Uttar Pradesh, 226 003, India. neetuaashi@yahoo.com. 2. Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India. profdkgupta@gmail.com. 3. Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India. 4. Molecular Biology Unit (Center for Advance Research), King George's Medical University, Lucknow, Uttar Pradesh, 226 003, India. 5. Department of Pediatric Surgery, King George's Medical University, Lucknow, 226 003, India. 6. Department of Plastic Surgery, King George's Medical University, Lucknow, 226 003, India.
Abstract
BACKGROUND: The genetic association of hypospadias-risk studies has been conducted in Caucasians, Chinese-Han populations and few in Indian populations. However, no comprehensive approach has been followed to assess genetic involvement in the severity of the disorder. METHODS: The study evaluated to establish the correlation between genotyped single nucleotide and copy number variants (SNPs/CNVs) and severity of hypospadias by an association in a total 30 SNPs in genes related to sex hormone-biosynthesis and metabolism; embryonic-development and phospholipase-D-signalling pathways on 138 surgery-confirmed hypospadias-cases from North India (84 penile and 28 cases of penoscrotal-hypospadias as compared with 31 cases of glanular + coronal), and analyzed and identified CNVs in four familial cases (18 members) and three paired-sporadic cases (6 members) using array-based comparative-genomic-hybridization and validated in 32 hypospadias samples by TaqMan assay. RESULTS: Based on odds ratio at 95% CI, Z Statistic and Significance Levels, STS gene-rs17268974 was associated with Penile-Hypospadias and 9-SNPs [seven-SNPs (rs5934740; rs5934842; rs5934913; rs6639811; rs3923341; rs17268974; rs5934937)] of STS gene; rs7562326-SRD5A2 and rs1877031-STARD3 were associated with penoscrotal-hypospadias. On aggregate analysis with p < 0.001, we identified homozygous-loss of Ch7:q34 (PRSS3P2, PRSS2). On validation in previously CNV-characterized and new (32 hypospadias cases), we identified PRSS3P2-loss in most of the grade 3 and 4 hypospadias. Hence, Grade 1 and 2 (coronal and granular) show no-PRSS3P2-loss and no-association with SNPs in STS; SRD5A2; STARD3-gene but Grade 3 and 4 (Penile and Penoscrotal) show PRSS3P2-loss accompanied with the association of SNPs in STS; SRD5A2; STARD3. CONCLUSIONS: Hence, homozygous-loss of PRSS3P2 accompanied with the association of STS; SRD5A2; STARD3 may link to the severity of the disease.
BACKGROUND: The genetic association of hypospadias-risk studies has been conducted in Caucasians, Chinese-Han populations and few in Indian populations. However, no comprehensive approach has been followed to assess genetic involvement in the severity of the disorder. METHODS: The study evaluated to establish the correlation between genotyped single nucleotide and copy number variants (SNPs/CNVs) and severity of hypospadias by an association in a total 30 SNPs in genes related to sex hormone-biosynthesis and metabolism; embryonic-development and phospholipase-D-signalling pathways on 138 surgery-confirmed hypospadias-cases from North India (84 penile and 28 cases of penoscrotal-hypospadias as compared with 31 cases of glanular + coronal), and analyzed and identified CNVs in four familial cases (18 members) and three paired-sporadic cases (6 members) using array-based comparative-genomic-hybridization and validated in 32 hypospadias samples by TaqMan assay. RESULTS: Based on odds ratio at 95% CI, Z Statistic and Significance Levels, STS gene-rs17268974 was associated with Penile-Hypospadias and 9-SNPs [seven-SNPs (rs5934740; rs5934842; rs5934913; rs6639811; rs3923341; rs17268974; rs5934937)] of STS gene; rs7562326-SRD5A2 and rs1877031-STARD3 were associated with penoscrotal-hypospadias. On aggregate analysis with p < 0.001, we identified homozygous-loss of Ch7:q34 (PRSS3P2, PRSS2). On validation in previously CNV-characterized and new (32 hypospadias cases), we identified PRSS3P2-loss in most of the grade 3 and 4 hypospadias. Hence, Grade 1 and 2 (coronal and granular) show no-PRSS3P2-loss and no-association with SNPs in STS; SRD5A2; STARD3-gene but Grade 3 and 4 (Penile and Penoscrotal) show PRSS3P2-loss accompanied with the association of SNPs in STS; SRD5A2; STARD3. CONCLUSIONS: Hence, homozygous-loss of PRSS3P2 accompanied with the association of STS; SRD5A2; STARD3 may link to the severity of the disease.
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