Table III.
Candidate genes responsible for Mendelian disorders that manifest POI.
| Gene | Location | Mendelian syndrome | Somatic features | Reference |
|---|---|---|---|---|
| FMR1 | Xq27.3 | Fragile X syndrome | Attention deficits, hyperactivity, social deficits, anxiety disorder, deficits in cognitive flexibility. | Reiss and Hall (2007) and Spath et al. (2010) |
| FOXL2 | 3q23 | Blepharophimosis-ptosis-epicanthus BPE type I syndrome, BPES I | BPES type I is a complex eyelid malformation associated with POI. The major features of the eyelid malformation involve (i) narrowed horizontal aperture of the eyelids (blepharophimosis), (ii) drooping of the upper eyelid (ptosis), (iii) the presence of a fold of skin arising from the lower eyelid that runs inward and upward (epicanthus inversus), and (iv) lateral displacement of the inner canthi (telecanthus). | Zlotogora et al. (1983) and Oley and Baraitser (1988) |
| GALT | 9p13 | Galactosemia | Cataracts, speech defects, poor growth, poor intellectual function, neurologic deficits (predominantly extrapyramidal findings with ataxia). | Schadewaldt et al. (2004) |
| AIRE | 21q22.3 | Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, APECED | Candidiasis, Addison's disease, hypoparathyroidism, type 1 diabetes, alopecia, vitiligo, ectodermal dystrophy, celiac disease and other intestinal dysfunctions, chronic atrophic gastritis, chronic active hepatitis, autoimmune thyroid disorders, pernicious anemia. | Fierabracci et al. (2012) |
| EIF2B | EIF2B2 -14q24.3; EIF2B4- 2p23.3; EIF2B5- 3q27.1 |
Central nervous system leukodystrophy and ovarian failure, ovarioleukodystrophy | Neurological disorder characterized by involvement of the white matter of the central nervous system. When Leukodystrophies associated with premature ovarian failure referred to as ovarioleukodystrophy. | Mathis et al. (2008) |
| POLG | 15q25 | Progressive external ophthalmoplegia, PEO | Manifestations range from involvement limited to the eyelids and extraocular muscles. | Graziewicz et al. (2007) |
| NOG | 17q22 | Proximal symphalangism, SYM1 | Ankylosis of the proximalinterphalangeal joints. | Kosaki et al. (2004) |
| PMM2 | 16p13 | PMM2-CDG CDG-1 (a previously known as congenital disorder of glycosylation type 1a) | Cerebellar dysfunction (ataxia, dysarthria, dysmetria), non-progressive cognitive impairment, stroke-like episodes, peripheral neuropathy with or without muscle wasting, absent puberty in females, small testes in males, retinitis pigmentosa, progressive scoliosis with truncal shortening, joint contractures, and premature aging | Sparks and Krasnewich (2005) |
|
HSD17B4 HARS2 CLPP LARS2 C10orf2 |
5q21 5q31.3 19p13.3 3p21.3 10q24 |
Perrault syndrome, PS | Sensorineural deafness in both males and females, and neurological manifestations in some patients. | Jenkinson et al. (2013), Morino et al. (2014), Pierce et al. (2011), Pierce et al. (2013) and Pierce et al. (2010) |
| BLM | 15q26.1 | Bloom syndrome | Chromosomal breakage leading to early onset of aging, short stature and elevated rates of most cancers. | Ellis and German (1996) |
| ATM | 11q22-q23 | Ataxia telangiectasia, A-T | Progressive cerebellar degeneration, telangiectasias, immunodeficiency, recurrent infections, insulin-resistant diabetes, premature aging, radiosensitivity, and high risk for epithelial cancers in surviving adults. | Gatti et al. (1991) and Su and Swift (2000) |
| WRN | 8p12 | Werner syndrome | Premature aging of the skin, vasculature, and bone and elevated rates of certain cancers, particularly sarcomas. | Epstein et al. (1966) |
| RECQL4 | 8q24.3 | Rothmund–Thomson syndrome, RTS | Cutaneous rash, sparse hair, small stature, skeletal and dental abnormalities, cataracts, premature aging, and an increased risk for cancer, especially malignancies originating from bone and skin tissue. | Wang et al. (2001) |
FMR1: Fragile X mental retardation 1; FOXL2: forkhead box L2; GALT: galactose 1-phosphate uridyl transferase; AIRE: autoimmune regulator; EIF2B: eukaryotic translation initiation factor; POLG: polymerase (DNA directed), gamma; NOG: noggin; PMM2: Phosphomannomutase 2; HSD17B4: Hydroxysteroid (17-beta) dehydrogenase 4; HARS2: Histidyl-tRNA synthetase 2, mitochondrial; CLPP: caseinolytic mitochondrial matrix peptidase proteolytic subunit; LARS2: leucyl-tRNA synthetase 2, mitochondrial; C10orf2: Chromosome 10 open reading frame 2; BLM: Bloom syndrome, RecQ helicase-like; ATM: ATM serine/threonine kinase; WRN: Werner syndrome, RecQ helicase-like; RECQL4: RecQ protein-like 4.