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Whole exome sequencing reveals novel LEPR frameshift mutation in severely obese children from Western India.

ABSTRACT: BACKGROUND:Obesity, especially early onset of obesity is a serious health concern in both developed and developing countries. This is further associated with serious comorbidities like a fatty liver disease, cardiovascular diseases, type-2 diabetes, obstructive sleep apnea, renal complications and respiratory problems. Many times early onset of obesity is linked with heritable monogenic, polygenic and syndromic forms. Globally, studies on roles of genes involved in early onset of obesity are limited. METHODS:Here in this study, a consanguineous family of Western Indian origin having four siblings, one unaffected and three affected with severe early onset of obesity was enrolled. Affected siblings also displayed comorbidities like mild to moderate obstructive sleep apnea, raised Renal Resistance Index, oliguria, and severe anemia. Whole Exome Sequencing (WES) of Trio with one affected and unaffected sibling was done. Data analysis was performed to check pathogenic mutation segregation in unaffected parents with affected and unaffected sibling. RESULTS:WES of trio identified novel frameshift mutation in the LEPR gene resulting in truncated leptin receptor (LEPR). The same mutation was confirmed in other affected siblings and two siblings of distant relatives by Sanger sequencing. The possible effects of truncating mutation in LEPR function by in silico analysis were also studied. CONCLUSION:Understanding genetic basis of obesity might provide a clue for better management and treatment in times to come. This work demonstrates identification of novel mutation in LEPR gene resulting into early onset of obesity. Discovery of novel, population-specific genomics markers will help population screening programs in creating base for possible therapeutic applications and prevention of this disease for next generations.

SUBMITTER: Bhatt A

PROVIDER: S-EPMC6625100 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Whole exome sequencing reveals novel LEPR frameshift mutation in severely obese children from Western India.

Bhatt Arpan A Purani Charul C Bhargava Poonam P Patel Komal K Agarbattiwala Tanvi T Puvar Apurvasinh A Shah Krati K Joshi Chaitanya G CG Dhamecha Nidhi N Prabhakar Mukund M Joshi Madhvi M

Molecular genetics & genomic medicine 20190508 7

<h4>Background</h4>Obesity, especially early onset of obesity is a serious health concern in both developed and developing countries. This is further associated with serious comorbidities like a fatty liver disease, cardiovascular diseases, type-2 diabetes, obstructive sleep apnea, renal complications and respiratory problems. Many times early onset of obesity is linked with heritable monogenic, polygenic and syndromic forms. Globally, studies on roles of genes involved in early onset of obesity ...[more]

PMID: 31070016

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Project description:RationaleGenetic elucidation of cone-dominated retinal dystrophies in Indian subcontinent is much needed to identify and catalog underlying genetic defects. In this context, the present study recruited a consanguineous Indian family affected with autosomal recessive cone dystrophy (CD). Considering the huge genetic heterogeneity and recessive inheritance of the disease, we chose to dissect out causal variant in this family by whole exome sequencing (WES).Patient concernsIn the recruited family, three of the six siblings had complaints of poor visual acuity, photophobia, and disturbed colour vision since early childhood. Fundus examination disclosed vascular attenuation and macular retinal pigment epithelium (RPE) changes in all the affected siblings, signifying degeneration of photoreceptor cells.DiagnosisComplete clinical investigation and electroretinography studies led to the diagnosis of cone dystrophy in three siblings of the family.InterventionsDetailed ophthalmic examination, including family history, visual function testing, and retinal imaging, was performed. We captured and sequenced exomes of 2 affected siblings and their mother using SureSelect Human All Exon V5 Kit on Illumina HiSeq 2000/2500 platform with 100 bp paired-end sequencing method. Candidates after data analysis were screened by segregation analysis and Sanger sequencing. Considering recessive inheritance and consanguinity in the pedigree, we attempted to map large loci homozygous by descent in the genome of patients using exome sequencing variants. Extensive protein modeling was carried out to assess possible consequences of the identified variant on the 3-dimensional structure of the protein.OutcomesWES generated more than 65,000 variants for each individual. Assuming recessive inheritance, 13,026 variants were selected. Further filtering on the basis of their position in gene, class, and minor allele frequency constricted the huge list to 12 rare variants. Finally, we ascertained a single base deletion c.1148delC (p.Thr383fs) in the gene CNGB3 as the causal variant. This is a recurrent frameshift mutation resulting in truncated CNGB3 protein. We mapped a large 15-Mb stretch of homozygous markers spanning the causal variant in the proband. The gene CNGB3 encodes modulatory subunit of cyclic nucleotide-gated channels in cone photoreceptors. Protein modeling reveals loss of 2 transmembrane helices and conserved CAP_ED domain in truncated CNGB3, which eventually is predicted to form nonfunctional channels and hamper phototransduction.LessonsWe have identified a recurrent mutation c.1148delC (p.Thr383fs) in CNGB3 for autosomal recessive CD. The present report provides the first description of CNGB3 mutation from India. It is also the foremost investigation of familial CD in Indian patients; therefore, it presents the primary genetic etiology of CD in India.

Project description:ObjectivesA 14-week-old female domestic longhair kitten presented with shifting lameness and disproportionately smaller size compared with a co-housed littermate.MethodsHematology and serum biochemical testing were conducted to investigate causes for delayed growth, and radiographs of the appendicular skeleton were obtained.ResultsThe afflicted kitten had marked hypocalcemia, mild hypophosphatemia and substantial elevations in alkaline phosphatase activity, as well as pathognomonic radiographic findings consistent with rickets. Skeletal changes and hypocalcemia prompted testing of concentrations of parathyroid hormone (PTH) and vitamin D metabolites. Endocrine testing demonstrated significant increases in serum concentrations of PTH and 1,25-dihydroxycholecalciferol (calcitriol), supporting a diagnosis of vitamin D-dependent rickets type 2. Provision of analgesia, supraphysiologic doses of calcitriol and calcium carbonate supplementation achieved normalization of the serum calcium concentration and restoration of normal growth, although some skeletal abnormalities persisted. Once skeletally mature, ongoing calcitriol supplementation was not required. Whole-exome sequencing (WES) was conducted to identify the underlying DNA variant. A cytosine deletion at cat chromosome position B4:76777621 in VDR (ENSFCAT00000029466:c.106delC) was identified and predicted to cause a stop codon in exon 2 (p.Arg36Glufs*18), disrupting >90% of the receptor. The variant was unique and homozygous in this patient and absent in the sibling and approximately 400 other cats for which whole-genome and whole-exome data were available.Conclusions and relevanceA unique, heritable form of rickets was diagnosed in a domestic longhair cat. WES identified a novel frameshift mutation affecting the gene coding for the vitamin D3 receptor, determining the likely causal genetic variant. Precision medicine techniques, including whole-exome and whole-genome sequencing, can be a standard of care in cats to identify disease etiologies, and to target therapeutics and personalize treatment.

Dataset Information

Whole exome sequencing reveals novel LEPR frameshift mutation in severely obese children from Western India.

Publications

Whole exome sequencing reveals novel LEPR frameshift mutation in severely obese children from Western India.

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