MedGen

Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis. [from GeneReviews]

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. [from OMIM]

Autosomal dominant tubulointerstitial kidney disease – UMOD (ADTKD-UMOD) is characterized by normal urinalysis and slowly progressive chronic kidney disease (CKD), usually first noted in the teen years and progressing to end-stage renal disease (ESRD) between the third and seventh decades. Hyperuricemia is often present from an early age, and gout (resulting from reduced kidney excretion of uric acid) occurs in the teenage years in about 8% of affected individuals and develops in 55% of affected individuals over time. [from GeneReviews]

Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely. Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels. Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids. Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH. Individuals with a more severe phenotype, often as a result of biallelic variants, can present with very significant elevations in LDL-C (>500 mg/dL), early-onset coronary artery disease (CAD; presenting as early as childhood in some), and calcific aortic valve disease. [from GeneReviews]

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome. [from GeneReviews]

Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (109400), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (see 276300). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (Crawford et al., 2007). Millard and De Braganca (2016) reviewed the histopathologic variants and molecular subgroups of medulloblastoma. Pretreatment prognosis of medulloblastoma has been refined by histopathologic subclassification into the following variants: large-cell medulloblastoma, anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity (MBEN). The latter 2 groups have been shown to have a significantly superior prognosis as compared to the large cell and anaplastic groups in young children. At the molecular level, medulloblastomas have been categorized into the following subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. Each subgroup is characterized by a unique set of genetics and gene expression as well as demographic and clinical features. [from OMIM]

Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements. Attacks are typically precipitated by coffee, tea, or alcohol; they can also be triggered by excitement, stress, or fatigue, or can be spontaneous. Attacks involve dystonic posturing with choreic and ballistic movements, may be accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and rarely occur more than once per day. Attack frequency, duration, severity, and combinations of symptoms vary within and among families. Age of onset is typically in childhood or early teens but can be as late as age 50 years. [from GeneReviews]

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome. [from GeneReviews]

Alzheimer's disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear between a person's thirties and mid-sixties, while the late-onset form appears during or after a person's mid-sixties. The early-onset form of Alzheimer's disease is much less common than the late-onset form, accounting for less than 10 percent of all cases of Alzheimer's disease.

Individuals with Alzheimer's disease usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Survival is usually shorter in individuals diagnosed after age 80 than in those diagnosed at a younger age. In Alzheimer's disease, death usually results from pneumonia, malnutrition, or general body wasting (inanition).

As the disorder progresses, some people with Alzheimer's disease experience personality and behavioral changes and have trouble interacting in a socially appropriate manner. Other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. People with Alzheimer's disease usually require total care during the advanced stages of the disease.

Memory loss is the most common sign of Alzheimer's disease. Forgetfulness may be subtle at first, but the loss of memory worsens over time until it interferes with most aspects of daily living. Even in familiar settings, a person with Alzheimer's disease may get lost or become confused. Routine tasks such as preparing meals, doing laundry, and performing other household chores can be challenging. Additionally, it may become difficult to recognize people and name objects. Affected people increasingly require help with dressing, eating, and personal care.

Alzheimer's disease is a degenerative disease of the brain that causes dementia, which is a gradual loss of memory, judgment, and ability to function. This disorder usually appears in people older than age 65, but less common forms of the disease appear earlier in adulthood. [from MedlinePlus Genetics]

Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with a gradually progressive movement disorder and neuropsychiatric symptoms. The movement disorder first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia. Seizures of various types occur frequently, some individuals experience chronic headache and vertigo; urinary urgency or incontinence may be present. [from GeneReviews]

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses. [from OMIM]

Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002). [from OMIM]

Pfeiffer syndrome is an autosomal dominant craniosynostosis syndrome with characteristic anomalies of the hands and feet. Three clinical subtypes, which have important diagnostic and prognostic implications, have been identified. Type 1, the classic syndrome, is compatible with life and consists of craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly, and variable syndactyly. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet, together with ankylosis of the elbows. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe, and the anterior cranial base is markedly short. Various visceral malformations have been found in association with type 3. Early demise is characteristic of types 2 and 3 (Cohen, 1993). Cohen and Barone (1994) further tabulated the findings in the 3 types of Pfeiffer syndrome. [from OMIM]

The Heidelberg histologic classification of renal cell tumors subdivides renal cell tumors into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most common documented genetic abnormalities (Kovacs et al., 1997). Malignant tumors are subclassified into common or conventional renal cell carcinoma (clear cell); papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and unclassified renal cell carcinoma. The common or conventional type accounts for about 75% of renal cell neoplasms and is characterized genetically by a highly specific deletion of chromosome 3p. Papillary renal cell carcinoma (see 605074) accounts for about 10% of renal cell tumors. Chromophobe renal cell carcinoma accounts for approximately 5% of renal cell neoplasms. Genetically, chromophobe RCC is characterized by a combination of loss of heterozygosity of chromosomes 1, 2, 6, 10, 13, 17, and 21 and hypodiploid DNA content. Collecting duct carcinoma accounts for about 1% of renal cell carcinoma. Renal cell carcinoma occurs nearly twice as often in men as in women; incidence in the United States is equivalent among whites and blacks. Cigarette smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one-third of cases. Obesity is also a risk factor, particularly in women. Other risk factors include hypertension, unopposed estrogen therapy, and occupational exposure to petroleum products, heavy metals, or asbestos (summary by Motzer et al., 1996). Genetic Heterogeneity of Renal Cell Carcinoma Germline mutation resulting in nonpapillary renal cell carcinoma of the clear cell and chromophobe type occurs in the HNF1A gene (142410) and the HNF1B gene (189907). Somatic mutations in renal cell carcinomas occur in the VHL gene (608537), the TRC8 gene (603046), the OGG1 gene (601982), the ARMET gene (601916), the FLCN gene (607273), and the BAP1 gene (603089). See also RCCX1 (300854) for a discussion of renal cell carcinoma associated with translocations of chromosome Xp11.2 involving the TFE3 gene (314310). For a discussion of papillary renal cell carcinoma, see RCCP1 (605074). Occurrence of Renal Cell Carcinoma in Other Disorders Von Hippel-Lindau syndrome (193300) is a familial multicancer syndrome in which there is a susceptibility to a variety of neoplasms, including renal cell carcinoma of clear cell histology and renal cysts. A syndrome of predisposition to uterine leiomyomas and papillary renal cell carcinoma has been reported (150800). Medullary carcinoma of the kidney is believed to arise from the collecting ducts of the renal medulla and is associated with sickle cell trait (603903) (Kovacs et al., 1997). Renal cell carcinoma occurs in patients with the Birt-Hogg-Dube syndrome (135150). Bertolotto et al. (2011) identified a missense mutation in the MITF (156845) gene that increases the risk of renal cell carcinoma with or without malignant melanoma (CMM8; 614456). [from OMIM]

Patients with deficiency of C8 suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes. Most such patients are discovered among those having their first episode of meningitis at ages older than 10 years (Ross and Densen, 1984). Two kinds of inherited C8 deficiency have been reported in humans: type I (C8D1), in which only C8 alpha and C8 gamma (C8G; 120930) are deficient, and type II (C8D2; 613789), in which only C8 beta (C8B; 120960) is deficient (Marcus et al., 1982; Tedesco et al., 1983). The 2 types are clinically indistinguishable (Ross and Densen, 1984). [from OMIM]

Early activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty, which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The timing of puberty is associated with risks of subsequent disease: earlier age of menarche in girls is associated with increased risk of breast cancer, endometrial cancer, obesity, type 2 diabetes, and cardiovascular disease. Central precocious puberty has also been associated with an increased incidence of conduct and behavior disorders during adolescence (summary by Abreu et al., 2013). Genetic Heterogeneity of Central Precocious Puberty Central precocious puberty-2 (CPPB2; 615346) is caused by mutation in the MKRN3 gene (603856) on chromosome 15q11. [from OMIM]

Patients with deficiency of C8 suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes. Most such patients are discovered among those having their first episode of meningitis at ages older than 10 years (Ross and Densen, 1984). Two types of inherited C8 deficiency have been reported in humans: type I (613790), in which only C8 alpha (C8A, 120950) and C8 gamma (C8G; 120930) are deficient, and type II, in which only C8 beta is deficient (Marcus et al., 1982; Tedesco et al., 1983). The 2 types are clinically indistinguishable (Ross and Densen, 1984). [from OMIM]

Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma). [from GeneReviews]

Premature ovarian failure is clearly a heterogeneous disorder. The terms 'hypergonadotropic ovarian failure' and 'hypergonadotropic ovarian dysgenesis' (see ODG1, 233300) have been used to indicate a group of disorders in which amenorrhea associated with elevated levels of serum gonadotropins occurs long before the age of 40 years (Coulam, 1982). Cytogenetic studies of X-chromosome aberrations have suggested that it is mainly the long arm of the X chromosome that is involved in defects of ovulation (Bione et al., 1998). Reviews Qin et al. (2015) reviewed the genetics of primary ovarian insufficiency (POI), also known as POF. They noted that causative genes had been identified in only 20 to 25% of POI cases. Rossetti et al. (2017) reviewed the genetics of primary ovarian insufficiency, noting that the significance of this disorder was increasing because of the increasing number of women desiring conception beyond 30 years of age, at which point POF prevalence is more than 1%. Genetic Heterogeneity of Premature Ovarian Failure Mutations in genes identified within a region defined as POF2 (Xq13.3-q21.1) have been found to cause other forms of POF: POF2A (300511) by mutation in the DIAPH2 gene (300108) and POF2B (300604) by mutation in the POF1B gene (300603). See also POF3 (608996), caused by mutation in the FOXL2 gene (605597) on chromosome 3q22; POF4 (see 300510), caused by mutation in the BMP15 gene (300247) on chromosome Xp11; POF5 (611548), caused by mutation in the NOBOX gene (610934) on chromosome 7q35; POF6 (612310), caused by mutation in the FIGLA gene (608697) on chromosome 2p13; POF7 (612964), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; POF8 (615723), caused by mutation in the STAG3 gene (608489) on chromosome 7q22; POF9 (615724), caused by mutation in the HFM1 gene (615684) on chromosome 1p22; POF10 (612885), caused by mutation in the MCM8 gene (608187) on chromosome 20p12; POF11 (616946), caused by mutation in the ERCC6 gene (609413) on chromosome 10q11; POF12 (616947), caused by mutation in the SYCE1 gene (611486) on chromosome 10q26; POF13 (617442), caused by mutation in the MSH5 gene (603382) on chromosome 6p21; POF14 (618014), caused by mutation in the GDF9 gene (601918) on chromosome 5q31; POF15 (618096), caused by mutation in the FANCM gene (609644) on chromosome 14q21; POF16 (618723), caused by mutation in the BNC1 gene (601930) on chromosome 15q25; POF17 (619146), caused by mutation in the XRCC2 gene (600375) on chromosome 7q36; POF18 (619203), caused by mutation in the C14ORF39 gene (617307) on chromosome 14q23; POF19 (619245), caused by mutation in the HSF2BP gene (604554) on chromosome 21q22; POF20 (609938), caused by mutation in the MSH4 gene (602105) on chromosome 1p31; POF21 (620311), caused by mutation in the TP63 gene (603273) on chromosome 3q28; POF22 (620548), caused by mutation in the KASH5 gene (618125) on chromosome 19q13; POF23 (620686), caused by mutation in the MEIOB gene (617670) on chromosome 16p13; POF24 (620840), caused by mutation in the SYCP2L gene (616799) on chromosome 6p24; and POF25 (621002), caused by mutation in the SPATA22 gene (617673) on chromosome 17p13. In 100 patients with primary or secondary amenorrhea before the age of 40 years, who also exhibited elevated FSH, Bouilly et al. (2016) screened for variants in 19 POF-associated or candidate genes. The authors noted that 8 of the 19 mutation-positive patients carried a genetic defect in more than 1 gene, and that patients with 2 or more variants tended to have a younger age of onset and were more likely have primary rather than secondary amenorrhea. Bouilly et al. (2016) suggested that digenicity and possibly oligogenicity may contribute to POF, noting that this might account for the phenotypic variability and incomplete penetrance that have been observed in patients with POF. [from OMIM]

Carvedilol (brand name Coreg) is used to treat heart failure and high blood pressure (hypertension). It is also used in patients who developed left ventricular dysfunction after having a heart attack (myocardial infarction, MI). In patients with cardiovascular disease, carvedilol is associated with improvements in quality of life, hospitalization rates, and survival. Carvedilol is a non-selective beta blocker (beta 1 and beta 2) and an alpha 1 blocker. It reduces the energy demands on the heart by blocking cardiac beta receptors, which decreases the heart rate and the force of heart contractions. Carvedilol lowers blood pressure by blocking alpha receptors on blood vessels, which relaxes and dilates blood vessels. CYP2D6 is one of the primary enzymes involved in activating and metabolizing carvedilol. Approximately 8% of Caucasians and 2% of most other populations have absent CYP2D6 activity and are predicted to be “CYP2D6 poor metabolizers.” The FDA-approved drug label for carvedilol states that plasma concentrations of carvedilol may be higher in CYP2D6 poor metabolizers compared to normal metabolizers, but does not discuss altering carvedilol dosing based on a patient’s CYP2D6 genotype. However, the label does state the dose of carvedilol should be individualized, and the dose should be monitored as it is gradually increased (up-titrated), based on tolerability and clinical response. The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) recommend that no action is needed for carvedilol and CYP2D6 genotype. For CYP2D6 poor metabolizers, DPWG states that the plasma concentration of carvedilol can be elevated, but this does not result in an increase in side effects. [from Medical Genetics Summaries]