Clinical and genetic characterization of congenital lipoid adrenal hyperplasia.

Disorders of steroid synthesis are a group of anomalies caused by defects in any step of conversion of cholesterol into steroid hormones. The disorders are characterized by defects leading to abnormalities of salt-water balance and/or sexual differentiation. Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of steroid synthesis disorder caused by the accumulation of cholesterol in the outer mitochondrial membrane due to steroidogenic acute regulatory protein (StAR) deficiency. Pathogenic sequence variants in the gene STAR encoding StAR protein leads to CLAH. In the present study, a Pakistani family was clinically diagnosed with the LAH phenotype. Sanger sequencing of STAR in the family revealed a novel homozygous nonsense mutation [c.295G>T, p.(Glu99*)] in the living affected individual. The study was designed to assist in carrier testing and prenatal diagnosis within the affected family. In addition, searching for common variants in the STAR gene would help in designing low-cost targeted variation testing in other patients.

Screening of 31 genes involved in monogenic forms of obesity in 23 Pakistani probands with early-onset childhood obesity: a case report.

BACKGROUND: Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population. METHODS: We identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands. RESULTS: We identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome. CONCLUSIONS: Mutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.

Identification of novel LEPR mutations in Pakistani families with morbid childhood obesity.

BACKGROUND: Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity. METHODS: Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping. RESULTS: Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C > G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R. CONCLUSIONS: The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment.

Association of 32 type 1 diabetes risk loci in Pakistani patients.

AIM: To identify risk alleles contributing towards type 1 diabetes in Pakistani patients. INTRODUCTION: Type 1 diabetes (T1D) is an autoimmune disease which is caused by destruction of insulin producing ß cells by immune system. Genetic predisposition as well as environmental factors contribute to its etiology. To date more than 40 risk loci have been identified for T1D. METHODOLOGY: A total of 191 family-based and unrelated T1D cases and controls were recruited. DNA was extracted and 32 genome-wide significant single nucleotide polymorphisms (SNPs) previously reported in Europeans were genotyped. Genotyping was performed using TaqMan SNP genotyping assays and the data was analyzed using FamCC software. RESULTS: Our results showed significant association of 10 single nucleotide polymorphisms (SNPs) with T1D at p<0.01, including HLA-DQA1/rs9272346, ERBB3/rs2292239, SIRPG/rs2281808, IL2-KIAA1109/rs4505848, GLIS3/rs7020673, CD226/rs763361, PTPN2/rs478582, IKZF1/rs10272724, BACH2/rs11755527, C6orf173/rs9388489, whereas 5 more SNPs showed their association at 0.01