Screening of 31 genes involved in monogenic forms of obesity in 23 Pakistani probands with early-onset childhood obesity: a case report.
Bardet-Biedl Syndrome
/ genetics
Body Mass Index
Child, Preschool
Codon, Nonsense
Consanguinity
Female
Genetic Association Studies
Genetic Predisposition to Disease
/ genetics
Genotype
Heterozygote
Homozygote
Humans
Leptin
/ genetics
Male
Mutation
Pakistan
Pediatric Obesity
/ genetics
Pedigree
Receptor, Melanocortin, Type 4
/ genetics
Receptors, Leptin
/ genetics
Autosomal recessive
Bardet-Biedl syndrome 9
Compound heterozygous
Consanguinity
Early-onset obesity
Monogenic obesity
Pakistani families
Journal
BMC medical genetics
ISSN: 1471-2350
Titre abrégé: BMC Med Genet
Pays: England
ID NLM: 100968552
Informations de publication
Date de publication:
05 09 2019
05 09 2019
Historique:
received:
18
03
2019
accepted:
29
08
2019
entrez:
7
9
2019
pubmed:
7
9
2019
medline:
4
12
2019
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31488071
doi: 10.1186/s12881-019-0886-8
pii: 10.1186/s12881-019-0886-8
pmc: PMC6727494
doi:
Substances chimiques
Codon, Nonsense
0
LEP protein, human
0
LEPR protein, human
0
Leptin
0
MC4R protein, human
0
Receptor, Melanocortin, Type 4
0
Receptors, Leptin
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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