MedGen

IMD31C is a disorder of immunologic dysregulation with highly variable manifestations resulting from autosomal dominant gain-of-function mutations in STAT1 (600555). Most patients present in infancy or early childhood with chronic mucocutaneous candidiasis (CMC). Other highly variable features include recurrent bacterial, viral, fungal, and mycoplasmal infections, disseminated dimorphic fungal infections, enteropathy with villous atrophy, and autoimmune disorders, such as hypothyroidism or diabetes mellitus. A subset of patients show apparently nonimmunologic features, including osteopenia, delayed puberty, and intracranial aneurysms. Laboratory studies show increased activation of gamma-interferon (IFNG; 147570)-mediated inflammation (summary by Uzel et al., 2013 and Sampaio et al., 2013). [from OMIM]

Childhood seizures associated with febrile episodes are relatively common and represent the majority of childhood seizures. A febrile convulsion is defined as a seizure event in infancy or childhood, usually occurring between 6 months and 6 years of age, associated with fever but without any evidence of intracranial infection or defined pathologic or traumatic cause (Nabbout et al., 2002). Although the majority of patients do not develop epilepsy, the risk of developing subsequent afebrile seizures is 5 to 7 times higher in those with a history of febrile seizures compared to the general population (Annegers et al., 1987; Hedera et al., 2006). The FEB1 locus maps to chromosome 8q13-q21. Genetic Heterogeneity of Familial Febrile Seizures See FEB2 (602477), caused by mutation in the HCN2 gene (602781) on chromosome 19p13; FEB3A (604403), caused by mutation in the SCN1A gene (182389) on chromosome 2q24; FEB4 (604352), caused by mutation in the ADGRV1 gene (602851) on chromosome 5q14; FEB8 (607681), caused by mutation in the GABRG2 gene (137164) on chromosome 5q31; and FEB11 (614418), caused by mutation in the CPA6 gene (609562) on chromosome 8q13. Several loci for familial febrile seizures have been identified: see FEB3B (613863) on chromosome 2q24; FEB5 (609255) on chromosome 6q22-q24; FEB6 (609253) on chromosome 18p11; FEB7 (611515) on chromosome 21q22; FEB9 (611634) on chromosome 3p24.2-p23; and FEB10 (612637) on chromosome 3q26. A phenotype termed 'generalized epilepsy with febrile seizures plus' (GEFS+; 604233) is a clinical subset of familial febrile convulsions in which affected individuals later develop afebrile seizures. GEFS+ is associated with mutations in several genes. Deprez et al. (2009) provided a review of the genetics of epilepsy syndromes starting in the first year of life, and included a diagnostic algorithm. [from OMIM]

Progressive intrahepatic cholestasis-7 with or without hearing loss (PFIC7) is an autosomal recessive liver disorder characterized by infantile-onset jaundice and itching associated with cholestasis, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and normal gamma glutamyltransferase (GGT). Liver biopsy shows hepatocellular and canalicular cholestasis with fibrotic changes. Many patients have resolution of the liver abnormalities with age, although some may have persistent liver enzyme abnormalities or splenomegaly. A subset of patients develops hearing loss in childhood between early infancy and the teenage years. Rifampicin may be effective for pruritis (summary by Maddirevula et al., 2019). For a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600). [from OMIM]

Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia (TRS). Clozapine is also used to reduce the risk of recurrent suicidal behavior in individuals with schizophrenia or schizoaffective disorder. Compared with typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill individuals who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood cell counts (WBC) and absolute neutrophil counts (ANC), and in the US, the FDA requires that individuals receiving clozapine be enrolled in a computer-based registry. There is also a propensity for clozapine use to induce metabolic effects, resulting in substantial weight gain. Clozapine is metabolized in the liver by the cytochrome P450 (CYP450) superfamily of enzymes. The CYP1A2 enzyme is the main CYP enzyme involved in clozapine metabolism, and CYP1A2 activity is a potential determinant of clozapine dose requirements. Other CYP enzymes involved in clozapine metabolism include CYP2D6, CYP3A4, and CYP2C19. The FDA-approved drug label states that a subset of the population (2–10%) have reduced activity of CYP2D6 (“poor metabolizers”[PMs]) and these individuals may develop higher than expected plasma concentrations of clozapine with typical standard doses. Therefore, the FDA states that a dose reduction may be necessary in individuals who are CYP2D6 PMs. However, the Dutch Pharmacogenetics Working Group (DPWG) does not recommend dose alterations based on CYP2D6 genotype, though the gene-drug interaction is acknowledged. The DPWG further states that there is not a gene-drug interaction between CYP1A2 and clozapine due to the limited effect of known genetic variants on CYP1A2 function. Consequently, neither the FDA nor the DPWG recommend dose alterations based on CYP1A2 genotype. Additionally, clozapine clearance is affected by gender, tobacco use, and ethnicity, with further contributions from pharmacologic interactions. Females have lower CYP1A2 enzyme activity than males. Non-smokers have lower CYP1A2 activity than smokers and Asians and Amerindians have lower activity than Caucasians. Clozapine clearance can also be affected by co-medications that induce or inhibit CYP1A2 and the presence of inflammation or obesity. [from Medical Genetics Summaries]

Renal hypomagnesemia-7 with or without dilated cardiomyopathy (HOMG7) is characterized primarily by renal salt wasting resulting in hypomagnesemia with secondary effects such as hypokalemia or hypocalcemia. Many patients develop nephrocalcinosis, although renal function is generally well-preserved. The age at onset is highly variable, ranging from infancy to young adulthood. A subset of patients develop severe dilated cardiomyopathy as early as in infancy, which may require heart transplant (Schlingmann et al., 2021). For a discussion of genetic heterogeneity of hypomagnesemia, see 602014. [from OMIM]

Ivacaftor is the first FDA-approved drug designed to target a specific defect of the CFTR protein found in a subset of Cystic fibrosis (CF) patients. Hundreds of different variants within the CFTR gene have been identified. The G551D variant (rs75527207 G>A) results in defective gating at the plasma membrane and, in combination with another disease-causing CFTR allele, can result in CF disease phenotypes. Ivacaftor is designed to potentiate G115D-CFTR to improve symptoms in CF patients who carry this variant. Therapeutic guidelines for ivacaftor based on CFTR genotype have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]