MedGen

Schizophrenia is highly heritable, as shown by family, twin, and adoption studies. For example, for identical twins, if one twin develops schizophrenia, the other twin has about a 50% chance of also developing the disease. The risk of the general population developing the schizophrenia is about 0.3-0.7% worldwide. The search for “schizophrenia genes” has been elusive. Initial linkage studies looked at parts of the genome associated with schizophrenia, and many candidate genes were identified, including APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53, and TPH1. However, some of these have later been questioned. Microdeletions and microduplications have been found to be three times more common in individuals with schizophrenia, compared to controls. Because these deletions and duplications are in genes that are overexpressed in pathways related to brain development, it is possible that the inheritance of multiple rare variants may contribute to the development of schizophrenia. Several genetic disorders feature schizophrenia as a clinical feature. The 22q11.2 Deletion Syndrome comprises many different syndromes, of which one of the most serious is DiGeorge syndrome. Children born with DiGeorge syndrome typically have heart defects, cleft palate, learning difficulties, and immune deficiency. Schizophrenia is a late manifestation, affecting around 30% of individuals. Microdeletions and duplications in chromosome 1, 2, 3, 7, 15 and 16 have also been associated with schizophrenia. In 2014, a genome-wide association study looked at the genomes of over 35,000 patients and 110,00 controls. The study identified 108 SNPs that were associated with schizophrenia, 83 of which had not been previously reported. As expected, many of these loci occurred in genes that are expressed in the brain. For example, the SNPs included a gene that encodes the dopamine D2 receptor, DRD2 (the target of antipsychotic drugs), and many genes involved in glutamine neurotransmitter pathways and synaptic plasticity (e.g., GRM3, GRIN2A, SRR, GRIA1). More surprisingly, however, associations were also enriched among genes expressed in tissues with important immune functions. In 2016, a study based on nearly 65,000 people investigated the association between schizophrenia and variation in the Major Histocompatibility Complex (MHC) locus—a region on chromosome 6 that is important for immune function. The study focused on the C4 gene (complement component 4) that exists as two distinct genes: C4A and C4B, which encode particularly structurally diverse alleles. The study found that the alleles which promoted greater expression of C4A in the brain were associated with a greater risk of schizophrenia. By using mice models, the study showed that C4 is involved in the elimination of synapses during brain maturation. In humans, “synaptic pruning” is most active during late adolescence, which coincides with the typical onset of symptoms of schizophrenia. It is therefore possible that the inheritance of specific C4A alleles could lead to “run away” synaptic pruning, increasing the risk of schizophrenia. Further research may even determine C4 as a potential therapeutic target. [from Medical Genetics Summaries]

Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by Ruiz-Perez et al., 2000). The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002). [from OMIM]

Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions (Sennvik et al., 2000). Terry and Davies (1980) pointed out that the 'presenile' form, with onset before age 65, is identical to the most common form of late-onset or 'senile' dementia, and suggested the term 'senile dementia of the Alzheimer type' (SDAT). Haines (1991) reviewed the genetics of AD. Selkoe (1996) reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimer disease. Theuns and Van Broeckhoven (2000) reviewed the transcriptional regulation of the genes involved in Alzheimer disease. Genetic Heterogeneity of Alzheimer Disease Alzheimer disease is a genetically heterogeneous disorder. See also AD2 (104310), associated with the APOE*4 allele (107741) on chromosome 19; AD3 (607822), caused by mutation in the presenilin-1 gene (PSEN1; 104311) on 14q; and AD4 (606889), caused by mutation in the PSEN2 gene (600759) on 1q31. There is evidence for additional AD loci on other chromosomes; see AD5 (602096) on 12p11; AD6 (605526) on 10q24; AD7 (606187) on 10p13; AD8 (607116) on 20p; AD9 (608907), associated with variation in the ABCA7 gene (605414) on 19p13; AD10 (609636) on 7q36; AD11 (609790) on 9q22; AD12 (611073) on 8p12-q22; AD13 (611152) on 1q21; AD14 (611154) on 1q25; AD15 (604154) on 3q22-q24; AD16 (300756) on Xq21.3; AD17 (615080) on 6p21.2; and AD18 (615590), associated with variation in the ADAM10 gene (602192) on 15q21. Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease (502500). Finally, there have been associations between AD and various polymorphisms in other genes, including alpha-2-macroglobulin (A2M; 103950.0005), low density lipoprotein-related protein-1 (LRP1; 107770), the transferrin gene (TF; 190000), the hemochromatosis gene (HFE; 613609), the NOS3 gene (163729), the vascular endothelial growth factor gene (VEGF; 192240), the ABCA2 gene (600047), and the TNF gene (191160) (see MOLECULAR GENETICS). [from OMIM]

MN antigens reside on GYPA, one of the most abundant red-cell glycoproteins. The M and N antigens are 2 autosomal codominant antigens encoded by the first 5 amino acids of GYPA and include 3 O-linked glycans as part of the epitope. M and N differ at amino acids 1 and 5, where M is ser-ser-thr-thr-gly, and N is leu-ser-thr-thr-glu. M is the ancestral GYPA allele and is common in all human populations and Old World apes. GYPA, glycophorin B (GYPB; 617923), and glycophorin E (GYPE; 138590) are closely linked on chromosome 4q31. The N terminus of GYPB is essentially identical to that of GYPA except that it always expresses the N antigen, denoted 'N' or N-prime. Antigens of the Ss blood group (111740) reside on GYPB, and recombination and gene conversion between GYPA, GYPB, and GYPE lead to hybrid glycophorin molecules and generation of low-incidence antigens. Thus, the MN and Ss blood groups are together referred to as the MNSs or MNS blood group system. The U antigen refers to a short extracellular sequence in GYPB located near the membrane. Recombination results in 3 glycophorin-null phenotypes: En(a-) cells lack GYPA due to recombination between GYPA and GYPB; GYPB-negative (S-s-U-) cells lack GYPB due to recombination in GYPB; and M(k) cells (M-N-S-s-U-) lack both GYPA and GYPB due to recombination between GYPA and GYPE. Individuals with glycophorin-null phenotypes have decreased sialic acid content and increased resistance to malarial infection (see 611162). GYPA and GYPB are not essential for red-cell development or survival, and GYPA- and GYPB-null phenotypes are not associated with anemia or altered red-cell function (review by Cooling, 2015). [from OMIM]

Blau syndrome is characterized by the triad of granulomatous arthritis, uveitis, and dermatitis. First described in 1985, it was considered to be distinct from sarcoidosis due to the early age of onset and autosomal dominant inheritance pattern. Published reports of sporadic cases of children with 'early-onset sarcoidosis' (EOS) with granulomatous involvement of different organs, primarily affecting joints, eyes, and skin, were suspected to represent the same disorder because the patients' characteristics were nearly identical. Subsequently, identical NOD2 mutations were identified in patients with Blau syndrome as well as in patients diagnosed with EOS, confirming earlier suspicions that they represented the same disease (summary by Borzutzky et al., 2010). Unlike older children diagnosed with sarcoidosis, these patients have no apparent pulmonary involvement; however, the disease is progressive and may result in severe complications such as blindness and/or joint destruction (Shetty and Gedalia, 1998). [from OMIM]

ADCY5 dyskinesia is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of chorea, athetosis, dystonia, myoclonus, or a combination of these. To date, affected individuals have had overlapping (but not identical) manifestations with wide-ranging severity. The facial movements are typically periorbital and perioral. The dyskinesia is prone to episodic or paroxysmal exacerbation lasting minutes to hours, and may occur during sleep. Precipitating factors in some persons have included emotional stress, intercurrent illness, sneezing, or caffeine; in others, no precipitating factors have been identified. In some children, severe infantile axial hypotonia results in gross motor delays accompanied by chorea, sometimes with language delays. The overall tendency is for the abnormal movements to stabilize in early middle age, at which point they may improve in some individuals; less commonly, the abnormal movements are slowly progressive, increasing in severity and frequency. [from GeneReviews]

Ss blood group antigens reside on the red-cell glycoprotein GYPB. The S and s antigens result from a polymorphism at amino acid 29 of GYPB, where S has met29 and s has thr29. The U antigen refers to a short extracellular sequence in GYPB located near the membrane. GYPB, glycophorin A (GYPA; 617922), and glycophorin E (GYPE; 138590) are closely linked on chromosome 4q31. Antigens of the MN blood group (111300) reside on GYPA. The M and N antigens differ at amino acids 1 and 5 of GYPA, where M is ser-ser-thr-thr-gly, and N is leu-ser-thr-thr-glu. The N terminus of GYPB is essentially identical to that of GYPA except that it always expresses the N antigen, denoted 'N' or N-prime. Recombination and gene conversion between GYPA, GYPB, and GYPE lead to hybrid glycophorin molecules and generation of low-incidence antigens. Thus, the MN and Ss blood groups are together referred to as the MNSs blood group system (see 111300). Recombination results in 3 glycophorin-null phenotypes: En(a-) cells lack GYPA due to recombination between GYPA and GYPB; GYPB-negative (S-s-U-) cells lack GYPB due to recombination in GYPB; and M(k) cells (M-N-S-s-U-) lack both GYPA and GYPB due to recombination between GYPA and GYPE. Individuals with glycophorin-null phenotypes have decreased sialic acid content and increased resistance to malarial infection (see 611162). GYPA and GYPB are not essential for red-cell development or survival, and GYPA- and GYPB-null phenotypes are not associated with anemia or altered red-cell function (review by Cooling, 2015). [from OMIM]

The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The major characteristics of kyphoscoliotic-type EDS are severe muscle hypotonia at birth, generalized joint laxity, scoliosis at birth, and scleral fragility and rupture of the ocular globe (Beighton et al., 1998). Nevo syndrome, previously thought to be a distinct entity, is identical to EDS type VI (Voermans et al., 2009). Genetic Heterogeneity of Ehlers-Danlos Syndrome, Kyphoscoliotic Type See EDSSKCL2 (614557), caused by mutation in the FKBP14 gene (614505). Classification of Ehlers-Danlos Syndromes The current classification of Ehlers-Danlos syndromes is based on a 2017 international classification described by Malfait et al. (2017), which recognizes 13 EDS subtypes. This classification revised the 'Villefranche classification' reported by Beighton et al. (1998). Beighton et al. (1998) reported on a revised nosology of the Ehlers-Danlos syndromes, designated the Villefranche classification. Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. Six main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of 'unspecified forms.' [from OMIM]

A fibrosarcoma that occurs in infants. It shares identical morphologic features with adult fibrosarcoma but carries the t(12;15)(p13;q25) translocation that results in ETV6-NTRK3 gene fusion. It usually affects the superficial and deep soft tissues of the extremities. The prognosis is generally much more favorable than for adult fibrosarcoma, and it rarely metastasizes. [from NCI]

A locally aggressive mesenchymal neoplasm composed either entirely or partly of an adipocytic proliferation showing at least focal nuclear atypia in both adipocytes and stromal cells. ""Atypical lipomatous tumor"" and ""well-differentiated liposarcoma"" are synonyms describing lesions that are morphologically and genetically identical. Amplification of MDM2 and/or CDK4 is almost always present. (WHO 2020) [from NCI]

An increased concentration of circulating alpha polypeptide of glycoprotein hormones (NCBI Gene 1081). This alpha subunit is common to luteinizing hormone (LH) , follicle stimulating hormone (FSH) , thyroid stimulating hormone (TSH) and human chorionic gonadotropin (hCG), which are glycoprotein hormones composed of an identical alpha subunit together with a beta subunit that confers biological specificity. The alpha subunit is used as a marker for tumors that produce these hormones. [from HPO]

Smith-McCort dysplasia (SMC) is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and trunk with barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest, features identical to those of Dyggve-Melchior-Clausen disease. Spinal cord compression due to atlantoaxial instability occurs in both SMC and DMC (Spranger et al., 1976; Nakamura et al., 1997). Genetic Heterogeneity of Smith-McCort Dysplasia Smith-McCort dysplasia-2 (SMC2; 615222) is caused by mutation in the RAB33B gene (605950) on chromosome 4q31. [from OMIM]

A rare neuropsychiatric disorder whose primary feature is the delusion that relatives or close acquaintances are not the persons that they are known to be. Visual recognition appears intact but familiar persons are thought be imposters, that is, they appear similar or identical to known individuals but are not. Most cases are seen in the context of a psychotic state. However, if manifested post-traumatically, the cause is most likely due to neurologic impairment. This disorder should be contrasted with prosopagnosia, in which an individual may not recognize a familiar person at all. [from NCI]

A malignant germ cell tumor arising from the ovary. Morphologically, it is identical to seminoma and consists of a monotonous population of germ cells with abundant pale cytoplasm and uniform nuclei. The stroma invariably contains chronic inflammatory cells, mostly T-lymphocytes. It responds to chemotherapy or radiotherapy and the prognosis relates to the tumor stage. [from NCI]

Main features described as symmetrical bradykinesia, predominantly axial rigidity, postural instability with early falls and cognitive decline with prominent features of frontal lobe dysfunction. Prevalence is unknown, but a higher number of cases have been described in the French West Indies. This form of atypical parkinsonism may be related to exposure to tropical plants containing mitochondrial complex I inhibitors. Guadelupian parkinsonism may actually be a tauopathy identical or closely related to progressive supranuclear palsy. Most patients are L-dopa unresponsive. [from SNOMEDCT_US]

A carcinoma with histological features identical to thyroid carcinoma, arising in ovarian mature teratoma with aberrant thyroid tissue (struma ovarii). [from NCI]

An autosomal recessive leukodystrophy sharing identical clinical and radiological features as X-linked Pelizaeus-Merzbacher disease. Prevalence is unknown. It is characterized by early-onset nystagmus, delayed motor milestones, progressive spasticity, ataxia, and diffuse leukodystrophy on magnetic resonance imaging. [from SNOMEDCT_US]