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 (ClinicalTrials.gov Identifier: NCT03374956); dietary supplements (ClinicalTrials.gov 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 most commonly associated with syndromic forms of obesity

GeneDisease Inheritance Symptoms
ALMS1 (606844) Alstrom syndrome (203800)                AR Progressive cone-rod dystrophy, sensorineural hearing loss, childhood obesity, hyperinsulinemia, type 2 diabetes mellitus
 ARL6 (608845)

Bardet-Biedl syndrome 3 (600151)

Retinitis pigmentosa 55 (613575)

Bardet-Biedl syndrome 1, modifier of (209900)
AR, digenic Retinal dystrophy, polydactyly, renal structural abnormalities, obesity 
 BBIP1 (613605) Bardet-Biedl syndrome 18 (615995) AR Retinitis pigmentosa, obesity, kidney failure, and cognitive disability
BBS1 (209901) Bardet-Biedl syndrome 1 (209900) AR, Digenic Retinitis pigmentosa, obesity, kidney dysfunction, polydactyly
BBS10 (610148) Bardet-Biedl syndrome 10 (615987)  AR Progressive retinal dystrophy, obesity, polydactyly, cognitive impairment
BBS12 (610683) Bardet-Biedl syndrome 12 (615989) AR Rod-cone dystrophy, polydactyly, obesity, hypogonadism, renal anomalies
BBS2 (606151)

Bardet-Biedl syndrome 2 (615981)

Retinitis pigmentosa 74 (616562)
AR Retinal degeneration, polydactyly, renal disease, hypogonadism, obesity
BBS4 (600374) Bardet-Biedl syndrome 4 (619982) AR Retinal dystrophy, obesity, polydactyly, renal dysfunction
BBS5 (603650) Bardet-Biedl syndrome 5 (619983)  AR Retinal dystrophy, postaxial polydactyly, obesity, renal dysfunction, hypogonadism 
 BBS7 (607590) Bardet-Biedl syndrome 7 (615984) AR  Retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity, renal anomalies 
BBS9/ PTHB1 (607968) Bardet-Biedl syndrome 9 (615986)  AR Obesity, polydactyly, renal anomalies, retinopathy, mental retardation
 CEP290 (610142)

Bardet-Biedl syndrome 14 (615991)

Joubert syndrome 5 (610188)

Leber congenital amaurosis 10 (611755)

Meckel syndrome 4 (611134)

Senior-Loken syndrome 6 (610189)
AR Retinitis pigmentosa, obesity, mental retardation, renal disease 
IFT27 (615870) Bardet-Biedl syndrome 19 (615996)  AR Obesity, intellectual disability, polydactyly, renal failure, retinitis pigmentosa, hypogonadism 
LZTFL1 (606568) Bardet-Biedl syndrome 17 (615994)  AR Retinitis pigmentosa, cognitive impairment, obesity, renal dysfunction, hypogenitalism 
MKKS (604896)

Bardet-Biedl syndrome 6 (605231)

McKusick-Kaufman syndrome (236700)
AR Postaxial polydactyly, retinitis pigmentosa, kidney defects, obesity 
MKS1 (609883)

Bardet-Biedl syndrome 13 (615990)

Joubert syndrome 28 (617121)

Meckel syndrome 1 (249000)
AR Postaxial polydactyly, retinitis pigmentosa, kidney defects, obesity 
MKS1 (609883)

Bardet-Biedl syndrome 13 (615990)

Joubert syndrome 28 (617121)

Meckel syndrome 1 (249000)
 AR Obesity, polydactyly, retinitis pigmentosa
 TRIM32 (602290) 

Bardet-Biedl syndrome 11 (615988)

Muscular dystrophy, limb-girdle, type 2H (254110)
 AR Obesity, polydactyly, renal anomalies, retinopathy, hypogonadism
TTC8 (608132)

Bardet-Biedl syndrome 8 (615985)

Retinitis pigmentosa 51 (613464)
AR Retinitis pigmentosa, obesity, postaxial polydactyly, hypogonadism 
SDCCAG8 (613524)

Bardet-Biedl syndrome 16 (615993)

Senior-Loken syndrome 7 (613615)
 AR Retinal degeneration, obesity, renal disease, cognitive impairment  
WDPCP (613580)  Bardet-Biedl syndrome 15 (615992) AR Pigmentary retinopathy, obesity, polydactyly, hypogenitalism, renal malformation and mental retardation
 DYRK1B (604556)  Abdominal obesity-metabolic syndrome 3 (615812) AD Coronary artery disease, central obesity, type 2 diabetes 
NR0B2 (604630) Mild early-onset obesity (601665) AD, AR, Multifactorial Obesity, early-onset diabetes
NTRK2 (600456)

Obesity, hyperphagia, and developmental delay (613886)

Early infantile epileptic encephalopathy 58 (617830)
AD Global developmental delay,  hyperphagia, obesity 
UCP3 (602044) Severe obesity and type II diabetes (601665) AD, AR, Multifactorial Obesity, adiposity
CUL4B (300304) Syndromic X-linked mental retardation (Cabezas type) (300354)  XLR Mental retardation, seizures, macrocephaly, central obesity, hypogonadism, pes cavus, tremor
GNAS (139320)

Pseudohypoparathyroidism Ia, b, c (103580; 603233; 612462)

Pseudopseudohypoparathyroidism (612463)

ACTH-independent macronodular adrenal hyperplasia (219080)

McCune-Albright syndrome (174800)

Progressive osseous heteroplasia (166350)

Pituitary adenoma 3 somatic (617686)
 AD Short stature, obesity, round facies, subcutaneous ossifications, brachydactyly 
MAGEL2 (605283) Schaaf-Yang syndrome (615547) AD Delayed development, intellectual disability, hypotonia, obesity 
PHF6 (300414) Borjeson-Forssman-Lehmann syndrome (301900)  XLR Severe mental defect, epilepsy, hypogonadism, marked obesity 
VPS13B (607817)  Cohen syndrome (216550)  AR Facial dysmorphism, microcephaly, truncal obesity, intellectual disability 
 SIM1 (603128) Severe obesity (601665) AD, AR, Multifactorial Diminished fetal activity, obesity, hypotonia, mental retardation, short stature, hypogonadism

Table 2: Overview of the genes most commonly associated with monogenic forms of obesity

GeneDisease Inheritance
MC4R (155541) Obesity (601665)                AD, AR, Multifactorial
LEP (614962) Obesity, morbid, due to leptin deficiency (614962) AR
LEPR (601007) Obesity, morbid, due to leptin receptor deficiency (614963) AR
PCSK1 (162150) Obesity with impaired prohormone processing (600955); Obesity, susceptibility to, BMIQ12 (612362) AR
POMC (176830) Obesity, adrenal insufficiency, and red hair due to POMC deficiency (609734); Obesity, early-onset, susceptibility to (601665) AD, AR, Multifactorial