Publications about genetic testing for metabolic disorders
  1. Obesity gene panel

Obesity gene panel

July 27, 2018

Disease summary:

Obesity is an increasingly common complex condition caused by several genetic and non-genetic risk factors and it is correlated with increased risks for diabetes type 2, heart diseases and cancers 1. It is a neuroendocrine condition caused by combined effects of both environmental and genetic risk factors and/or predispositions 5, 6, 7.

The genetic causes of obesity can be classified as monogenic and syndromic forms8. Syndromic forms of obesity are caused by the genes: ALMS1, ARL6, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CEP290, CUL4B, DYRK1B, GNAS, IFT27, LEP, LEPR, LZTFL1, MAGEL2, MC4R, MKKS, MKS1, NR0B2, NTRK2, PCSK1, PHF6, POMC, SDCCAG8, SIM1, TRIM32, TTC8, UCP3, VPS13B, WDPCP (Table 1). Monogenic forms of obesity are associated with pathogenic variants in the MC4R, LEP, LEPR, PCSK1 and POMC genes (Table 2). 

Autosomal dominant, autosomal recessive, digenic recessive, X-linked

Increasing prevalence for non-genetic forms of obesity

Major clinical symptoms 1:

  • Severe early-onset obesity and hyperphagia
  • Increased linear growth and delayed puberty
  • Psychological changes (depression, anxiety and other)
  • Hyperinsulinemia and/or hypocortisolemia                                                          

Overview of symptoms in specific syndromic forms of obesity is given in Table 1.

  • Presence of abnormal obesity from the earliest ages
  • Laboratory analyses of serum and urine showing abnormal levels of glucose, lipids, and other substances
  • Positive family history of disease
  • Identification of a pathogenic variant in one of the associated genes for syndromic (Table 1) and monogenic forms of obesity (Table 2).

Depending on the genetic background of obesity, the treatment is based on changes in the lifestyle or additional managements, including the following:

  • Diet, exercise and behavioral modification
  • Pharmacotherapy, monitoring of blood sugar levels, blood pressure and other complications
  • Ongoing clinical trials are in progress, testing new potential drugs for obesity, including: Phentermine-Topiramate; Liraglutide; Naltrexone/bupropion; Phentermine ( Identifier: NCT03374956); dietary supplements ( Identifier: NCT02733484) and others.
  • Type 2 diabetes mellitus
  • Cushing syndrome
  • Hypothyroidism
  • Insulinoma
  • Kallmann syndrome and idiopathic hypogonadotropic hypogonadism
  • Generalized lipodystrophy

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • Obesity NGS Panel which includes sequencing of the genes ALMS1, ARL6, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CEP290, CUL4B, DYRK1B, GNAS, IFT27, LEP, LEPR, LZTFL1, MAGEL2, MC4R, MKKS, MKS1, NR0B2, NTRK2, PCSK1, PHF6, POMC, SDCCAG8, SIM1, TRIM32, TTC8, UCP3, VPS13B, WDPCP
  • Obesity NGS Panel + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data for the above genes
  • Individuals with a positive family history of obesity
  • Individuals with most common symptoms of obesity (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of obesity can allow for genetic counseling and may direct medical management.

Table 1: Overview of the genes included in Obesity panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ALMS1 606844 Alstrom syndrome AR 59
ARL6 608845 Bardet-Biedl syndrome 1, modifier of; Bardet-Biedl syndrome 3; ?Retinitis pigmentosa 55 AR, Digenic R 6
BBIP1 613605 ?Bardet-Biedl syndrome 18 AR 1
BBS1 209901 Bardet-Biedl syndrome 1 AR, Digenic R 14
BBS10 610148 Bardet-Biedl syndrome 10 AR 12
BBS12 610683 Bardet-Biedl syndrome 12 AR 8
BBS2 606151 Bardet-Biedl syndrome 2; Retinitis pigmentosa 74 AR 16
BBS4 600374 Bardet-Biedl syndrome 4 AR 10
BBS5 603650 Bardet-Biedl syndrome 5 AR 27
BBS7 607590 Bardet-Biedl syndrome 7 AR 16
BBS9 607968 Bardet-Biedl syndrome 9 AR 23
CEP290 610142 Joubert syndrome 5; Senior-Loken syndrome 6; Meckel syndrome 4; Leber congenital amaurosis 10; ?Bardet-Biedl syndrome 14 AR 51
CUL4B 300304 Mental retardation, X-linked, syndromic 15 (Cabezas type) XL R 4
DYRK1B 604556 Abdominal obesity-metabolic syndrome 3 AD 0
GNAS 139320 Pseudohypoparathyroidism Ia; Osseous heteroplasia, progressive; McCune-Albright syndrome, somatic, mosaic; ACTH-independent macronodular adrenal hyperplasia; Pseudohypoparathyroidism Ib; Pseudohypoparathyroidism Ic; Pseudopseudohypoparathyroidism; Pituitary adenoma 3, multiple types, somatic AD, Isolated cases 14
IFT27 615870 ?Bardet-Biedl syndrome 19 AR 0
LEP 164160 Obesity, morbid, due to leptin deficiency AR 3
LEPR 601007 Obesity, morbid, due to leptin receptor deficiency 0
LZTFL1 606568 Bardet-Biedl syndrome 17 AR 6
MAGEL2 605283 Schaaf-Yang syndrome AD 6
MC4R 155541 Obesity, autosomal dominant AD, AR, MF 0
MKKS 604896 McKusick-Kaufman syndrome; Bardet-Biedl syndrome 6 AR 6
MKS1 609883 Meckel syndrome 1; Bardet-Biedl syndrome 13; Joubert syndrome 28 AR 7
NR0B2 604630 Obesity, mild, early-onset AD, AR, MF 0
NTRK2 600456 Obesity, hyperphagia, and developmental delay; Epileptic encephalopathy, early infantile, 58 AD 0
PCSK1 162150 Obesity with impaired prohormone processing; Obesity, susceptibility to, BMIQ12 AR 0
PHF6 300414 Borjeson-Forssman-Lehmann syndrome XL R 3
POMC 176830 Obesity, early-onset, susceptibility to; Obesity, adrenal insufficiency, and red hair due to POMC deficiency AD, AR, MF 2
SDCCAG8 613524 Senior-Loken syndrome 7; Bardet-Biedl syndrome 16 AR 11
SIM1 603128 Obesity, severe AD, AR, MF 1
TRIM32 602290 Muscular dystrophy, limb-girdle, type 2H; ?Bardet-Biedl syndrome 11 AR 2
TTC8 608132 ?Retinitis pigmentosa 51; Bardet-Biedl syndrome 8 AR 11
UCP3 602044 Obesity, severe, and type II diabetes AD, AR, MF 1
VPS13B 607817 Cohen syndrome AR 20
WDPCP 613580 ?Congenital heart defects, hamartomas of tongue, and polysyndactyly; ?Bardet-Biedl syndrome 15 AR 7