Type 2 diabetes mellitus is distinct from maturity-onset diabetes of the young (see 606391) in that it is polygenic, characterized by gene-gene and gene-environment interactions with onset in adulthood, usually at age 40 to 60 but occasionally in adolescence if a person is obese. The pedigrees are rarely multigenerational. The penetrance is variable, possibly 10 to 40% (Fajans et al., 2001). Persons with type 2 diabetes usually have an obese body habitus and manifestations of the so-called metabolic syndrome (see 605552), which is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia. Genetic Heterogeneity of Susceptibility to Type 2 Diabetes Susceptibility to T2D1 (601283) is conferred by variation in the calpain-10 gene (CAPN10; 605286) on chromosome 2q37. The T2D2 locus (601407) on chromosome 12q was found in a Finnish population. The T2D3 locus (603694) maps to chromosome 20. The T2D4 locus (608036) maps to chromosome 5q34-q35. Susceptibility to T2D5 (616087) is conferred by variation in the TBC1D4 gene (612465) on chromosome 13q22. A mutation has been observed in hepatocyte nuclear factor-4-alpha (HNF4A; 600281.0004) in a French family with NIDDM of late onset. Mutations in the NEUROD1 gene (601724) on chromosome 2q32 were found to cause type 2 diabetes mellitus in 2 families. Mutation in the GLUT2 glucose transporter was associated with NIDDM in 1 patient (138160.0001). Mutation in the MAPK8IP1 gene, which encodes the islet-brain-1 protein, was found in a family with type 2 diabetes in individuals in 4 successive generations (604641.0001). Polymorphism in the KCNJ11 gene (600937.0014) confers susceptibility. In French white families, Vionnet et al. (2000) found evidence for a susceptibility locus for type 2 diabetes on 3q27-qter. They confirmed the diabetes susceptibility locus on 1q21-q24 reported by Elbein et al. (1999) in whites and by Hanson et al. (1998) in Pima Indians. A mutation in the GPD2 gene (138430.0001) on chromosome 2q24.1, encoding mitochondrial glycerophosphate dehydrogenase, was found in a patient with type 2 diabetes mellitus and in his glucose-intolerant half sister. Mutations in the PAX4 gene (167413) have been identified in patients with type 2 diabetes. Triggs-Raine et al. (2002) stated that in the Oji-Cree, a gly319-to-ser change in HNF1-alpha (142410.0008) behaves as a susceptibility allele for type 2 diabetes. Mutation in the HNF1B gene (189907.0007) was found in 2 Japanese patients with typical late-onset type 2 diabetes. Mutations in the IRS1 gene (147545) have been found in patients with type 2 diabetes. A missense mutation in the AKT2 gene (164731.0001) caused autosomal dominant type 2 diabetes in 1 family. A (single-nucleotide polymorphism) SNP in the 3-prime untranslated region of the resistin gene (605565.0001) was associated with susceptibility to diabetes and to insulin resistance-related hypertension in Chinese subjects. Susceptibility to insulin resistance has been associated with polymorphism in the TCF1 (142410.0011), PPP1R3A (600917.0001), PTPN1 (176885.0001), ENPP1 (173335.0006), IRS1 (147545.0002), and EPHX2 (132811.0001) genes. The K121Q polymorphism of ENPP1 (173335.0006) is associated with susceptibility to type 2 diabetes; a haplotype defined by 3 SNPs of this gene, including K121Q, is associated with obesity, glucose intolerance, and type 2 diabetes. A SNP in the promoter region of the hepatic lipase gene (151670.0004) predicts conversion from impaired glucose tolerance to type 2 diabetes. Variants of transcription factor 7-like-2 (TCF7L2; 602228.0001), located on 10q, have also been found to confer risk of type 2 diabetes. A common sequence variant, rs10811661, on chromosome 9p21 near the CDKN2A (600160) and CDKN2B (600431) genes has been associated with risk of type 2 diabetes. Variation in the PPARG gene (601487) has been associated with risk of type 2 diabetes. A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to NIDDM. Variation in the KCNJ15 gene (602106) has been associated with T2D in lean Asians. Variation in the SLC30A8 gene (611145) has been associated with susceptibility to T2D. Variation in the HMGA1 gene (600701.0001) is associated with an increased risk of type 2 diabetes. Mutation in the MTNR1B gene (600804) is associated with susceptibility to type 2 diabetes. Protection Against Type 2 Diabetes Mellitus Protein-truncating variants in the SLC30A8 (611145) have been associated with a reduced risk for T2D.

An autosomal recessive subtype of cerebrooculofacioskeletal syndrome caused by mutation(s) in the ERCC6 gene, encoding DNA excision repair protein ERCC-6.

SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deeply set eyes), Rieger anomaly, and teething delay. It is now recognized that the features most consistently observed in SHORT syndrome are mild intrauterine growth restriction (IUGR); mild to moderate short stature; partial lipodystrophy (evident in the face, and later in the chest and upper extremities, often sparing the buttocks and legs); and a characteristic facial gestalt. Insulin resistance may be evident in mid-childhood or adolescence, although diabetes mellitus typically does not develop until early adulthood. Other frequent features include Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis, delayed dentition and other dental issues, and sensorineural hearing loss.

A rare familial partial lipodystrophy with characteristics of adult onset of distal lipoatrophy with gluteofemoral fat loss, as well as increased fat accumulation in the face and trunk and visceral adiposity. Additional manifestations include diabetes mellitus, atherogenic dyslipidemia, eyelid xanthelasma, arterial hypertension, cardiovascular disease, hepatic steatosis, acanthosis nigricans on axilla and neck, hirsutism, and muscular hypertrophy of the lower limbs. Caused by heterozygous mutation in the PPARG gene on chromosome 3p25.

This syndrome is characterised by the association of acanthosis nigricans, insulin resistance, severe muscle cramps and acral hypertrophy.

Congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome, is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, and early onset of diabetes (Garg, 2004). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014). Genetic Heterogeneity of Bardet-Biedl Syndrome BBS2 (615981) is caused by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by mutation in the MKKS gene on 20p12 (604896); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q21 (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23; BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, BBS15 (615992), by mutation in the WDPCP gene (613580) on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43; BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (619471), by mutation in the IFT172 gene (607386) on 9p21; BBS21 (617406), by mutation in the CFAP418 gene (614477) on 8q22; and BBS22 (617119), by mutation in the IFT74 gene (608040) on 9p21. The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001). Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation.

Cortisone reductase deficiency is a disorder in which there is a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase, encoded by the HSD11B1 gene. Purified 11-beta-HSD acts readily as a dehydrogenase, inactivating cortisol to cortisone; however, in the presence of a high NADPH/NADP+ ratio, generated in vivo through the activity of microsomal hexose-6-phosphate dehydrogenase (H6PD; 138090), 11-beta-HSD switches to ketoreductase activity and generates active glucocorticoid. Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting later with hirsutism, oligomenorrhea, and infertility. Biochemically, CORTRD is diagnosed through the assessment of urinary cortisol and cortisone metabolites and consists of measuring the ratio of tetrahydrocortisol (THF) plus 5-alpha-THF to tetrahydrocortisone (THE), which in CORTRD patients is typically less than 0.1 (reference range, 0.7 to 1.2) (summary by Lawson et al., 2011). For a discussion of genetic heterogeneity of cortisone reductase deficiency, see CORTRD1 (604931).

Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance, and metabolic abnormalities including insulin resistance and diabetes mellitus. Sensorineural deafness occurs late in the first or second decades of life (summary by Weedon et al., 2013).

Lipodystrophies are rare disorders characterized by loss of body fat from various regions and predisposition to metabolic complications of insulin resistance and lipid abnormalities. FPLD7 is an autosomal dominant disorder with a highly variable phenotype. Additional features, including early-onset cataracts and later onset of spasticity of the lower limbs, have been noted in some patients (summary by Garg et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

A rare, genetic form of obesity characterized by morbid obesity, hypertension, type 2 diabetes mellitus and dyslipidemia leading to early coronary disease, myocardial infarction and congestive heart failure. Intellectual disability and decreased sperm counts or azoospermia have also been reported.

In addition to classic type 1 (see 222100) and type 2 (see 125853) diabetes mellitus, atypical presentations are seen, particularly in populations of African ancestry. Ketosis-prone diabetes, the most common atypical form, is characterized by an acute initial presentation with severe hyperglycemia and ketosis, as seen in classic type 1 diabetes, but after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies show a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic beta-cell autoimmunity is a rare finding, and association with type 1 susceptibility HLA alleles is variable (Sobngwi et al., 2002).

Familial partial lipodystrophy type 6 (FPLD6) is characterized by abnormal subcutaneous fat distribution, with variable excess accumulation of fat in the face, neck, shoulders, axillae, back, abdomen, and pubic region, and reduction in subcutaneous fat of the lower extremities. Progressive adult-onset myopathy is seen in some patients, and there is variable association with diabetes, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and hepatic steatosis (Zolotov et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

In patients with SSMED, short stature and microcephaly are apparent at birth, and there is progressive postnatal growth failure. Endocrine dysfunction, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus, is present in affected adults. Progressive ataxia has been reported in some patients, with onset ranging from the second to fifth decade of life. In addition, a few patients have developed tumors, suggesting that there may be a predisposition to tumorigenesis. In contrast to syndromes involving defects in other components of the nonhomologous end-joining (NHEJ) complex (see, e.g., 606593), no clinically overt immunodeficiency has been observed in SSMED, although laboratory analysis has revealed lymphopenia or borderline leukopenia in some patients (Murray et al., 2015; Bee et al., 2015; de Bruin et al., 2015; Guo et al., 2015).

Any Seckel syndrome in which the cause of the disease is a mutation in the NSMCE2 gene.

Patients with biallelic mutations in the ADCY3 gene show hyperphagia within the first 2 years of life and develop severe obesity. Other features include hyposmia or anosmia, and some patients exhibit mild to moderate intellectual disability (Saeed et al., 2018).

Familial partial lipodystrophy type 4 is an autosomal dominant metabolic disorder characterized by childhood or young adult onset of loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin-resistant diabetes mellitus, hypertriglyceridemia, and hypertension (summary by Gandotra et al., 2011). Other features may include hepatic steatosis, acanthosis nigricans, polycystic ovary syndrome, and renal disease (summary by Chen et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

Marbach-Rustad progeroid syndrome (MARUPS) is characterized by progeroid appearance with little subcutaneous fat and triangular facies, growth retardation with short stature, hypoplastic mandible crowded with unerupted supernumerary teeth, and cerebellar intention tremor. Psychomotor development is normal. Although features are reminiscent of Hutchinson-Gilford progeria syndrome (HGPS; 176670), MARUPS is less severe, with a relatively good prognosis. Two patients have been reported (Marbach et al., 2019).

Congenital generalized lipodystrophy type 5 (CGL5) is an autosomal recessive metabolic disorder characterized by childhood onset of lipodystrophy, severe nonalcoholic fatty liver disease, dyslipidemia, hypertriglyceridemia, low HDL, and insulin-resistant diabetes mellitus. Affected individuals also have short stature (Payne et al., 2014). For a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Osteogenesis imperfecta type XXIII (OI23) is a mild recessive form of OI, characterized by osteopenia with or without recurrent fractures, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regress after early childhood; osteopenia persists, but responds well to bisphosphonate (Tuysuz et al., 2023).