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| Additional findings_Adult v1.72 | PHYH |
Zornitza Stark gene: PHYH was added gene: PHYH was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: PHYH was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PHYH were set to Refsum disease, MIM# 266500 Review for gene: PHYH was set to GREEN Added comment: MODERATE actionability by ClinGen. Adult forms described. RD is clinically characterized by anosmia (absence of smell) and early-onset retinitis pigmentosa (RP), which are both universal findings with variable combinations of peripheral neuropathy, cerebellar ataxia, deafness, ichthyosis, and short metatarsals and metacarpals. Treatment for many manifestations of RD are supportive: hydrating creams for ichthyosis, drugs for cardiac arrhythmias and cardiomyopathy, cataract surgery, and implantation of cochlear implants. The standard therapy for prevention of primary manifestations is to lower plasma phytanic acid (PA) levels by dietary restriction of PA. For acute care or when diet is not sufficient, PA may be eliminated by plasmapheresis or lipid apheresis. These therapies have been found to reduce plasma PA concentrations by 50-70%, and possibly stabilize or improve symptoms of ichthyosis, sensory neuropathy, ataxia, improve cardiac arrhythmia, and extreme weakness. It is uncertain whether either treatment affects the progression of the anosmia, deafness, or RP and other ocular outcomes. Sources: Expert list |
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| Additional findings_Adult v1.68 | CPT2 |
Zornitza Stark gene: CPT2 was added gene: CPT2 was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: CPT2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CPT2 were set to CPT II deficiency, myopathic, stress-induced, MIM# 255110 Review for gene: CPT2 was set to GREEN Added comment: Variable age of onset and severity. Adult form tends to be myopathic. The recommendation for treatment of CPT II deficiency is to follow current treatment for long-chain FAO disorders: - Reduce the amount of long-chain dietary fat (<20%) while covering the need for essential fatty acids - Provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines - Provide a large fraction of calories as carbohydrates (70%) to reduce body fat utilization and prevent hypoglycaemia - Provide approximately one third of calories as even-chain medium chain triglycerides (MCT) Sources: Expert list |
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| Additional findings_Adult v1.52 | SLC22A5 |
Zornitza Stark gene: SLC22A5 was added gene: SLC22A5 was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: SLC22A5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC22A5 were set to Carnitine deficiency, systemic primary, MIM# 212140 Review for gene: SLC22A5 was set to GREEN Added comment: MODERATE actionability in adults by ClinGen. Adulthood presentation is associated with minor symptoms like fatigue and decreased stamina, but dilated cardiomyopathy and arrhythmias and sudden cardiac death have also been reported. The main treatment for CDSP is lifelong oral levocarnitine (L-carnitine) supplementation. The benefit of treatment in asymptomatic adults is less well established, but is hoped it may prevent cardiac events and decompensations. Metabolic decompensation and hypoglycaemic episodes are treated with glucose in addition to carnitine supplementation. Referral to cardiology for cardiomyopathy assessment is recommended. Sources: Expert list |
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| Additional findings_Adult v1.40 | CBS |
Zornitza Stark gene: CBS was added gene: CBS was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: CBS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CBS were set to Homocystinuria, B6-responsive and nonresponsive types, MIM# 236200 Review for gene: CBS was set to GREEN Added comment: MODERATE actionability in adults by ClinGen. Progressive disorder with variable range of onset of clinical manifestations, including adult presentations. Diagnosis can be delayed. Thromboembolism is the major cause of disability and death. Pregnancy and postpartum period present heightened risk. The aim of treatment is to prevent all complications (early and late) by controlling the elevated total plasma homocysteine (tHcy) concentrations by using one or a combination of treatments. This includes assessment of whether the disorder is pyridoxine-responsive and dietary measures. Betaine and anti-coagulants can be used as adjunct treatments. For pathogenic variants commonly present in the homozygous state, there are a few well established genotype-phenotype correlations with good concordance between pyridoxine responsiveness and a milder clinical phenotype. For example, one of the most the common variants, c.833T>C (p.I278T), is pan ethnic, accounts for nearly 24% of all pathogenic variants, and when homozygous leads to a mild pyridoxine-responsive type of CBS deficiency. Sources: Expert list |
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| Additional findings_Adult v1.38 | ACADM |
Zornitza Stark gene: ACADM was added gene: ACADM was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: ACADM was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ACADM were set to Acyl-CoA dehydrogenase, medium chain, deficiency of, MIM# 201450 Review for gene: ACADM was set to GREEN Added comment: An individual with MCAD deficiency is at risk of metabolic decompensation when their energy needs are not met with exogenous sources and have to rely on stored fat, such as during prolonged fasting or periods of higher energy demand. Clinical symptoms in a previously apparently healthy individual with MCAD deficiency include hypoketotic hypoglycemia and nausea or vomiting that may progress to lethargy, seizures, coma, and even sudden death. Symptoms may be triggered by a common illness, fasting, excessive drug or alcohol intake, diarrhea, or vomiting and can progress to seizures or coma within 1-2 hours of onset; on occasion, seizures or coma may be the presenting sign. Hepatomegaly and liver disease are often present during an acute episode. Uncontrolled metabolic decompensation can increase the risk of neurological findings secondary to brain injury (e.g. loss of developmental milestones) and chronic muscular weakness. Late-onset presentations have been described in adults after prolonged fasting, including after fasting for surgery, or with alcohol intoxication, often with fatal results. The mainstay for prevention of primary manifestations in asymptomatic patients with MCAD deficiency is avoidance of prolonged fasting. There is a risk of metabolic decompensation during surgery, particularly if catabolism is precipitated by fasting and surgery. It is important to minimize catabolism by providing adequate amounts of carbohydrate (orally or intravenously) prior to and during surgery. Low-dose L-carnitine supplementation is recommended when carnitine levels are below the normal range. Individuals with MCAD deficiency may develop a secondary carnitine deficiency as excess medium chain fatty acids bind to free carnitine and are excreted. Individuals should be provided with an emergency protocol/letter to carry at all times. They should be strongly advised to seek medical attention if the individual with MCAD deficiency has an acute illness accompanied by poor intake, vomiting, and/or lethargy. The letter should contain patient identifiers, description of the disorder, emergency treatment protocol, and contact information for the metabolic specialist. Pregnant women should receive supplemental carnitine to account for reduced plasma free carnitine levels during pregnancy, though free carnitine may still not reach pre-pregnancy levels. Intravenous glucose should be started as soon as labour begins and continued until the patient has adequate oral intake and can maintain normoglycaemia. Sources: Expert list |
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| Additional findings_Adult v1.34 | GBA |
Zornitza Stark gene: GBA was added gene: GBA was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: GBA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GBA were set to Gaucher disease, type I MIM#230900 Review for gene: GBA was set to GREEN Added comment: Gaucher disease type 1 can present at any age. GD is a lysosomal storage disorder caused by a deficiency of glucocerebrosidase which results in the multisystemic accumulation of glucosylceramide-laden macrophages (Gaucher cells) in various tissues: spleen, liver, bone marrow, bone mineral, and less often the lungs, skin, eyes, kidneys, lymphatic system, and heart. The spectrum of clinical manifestations and symptoms includes hepatosplenomegaly (HSM), abdominal discomfort and distension, skeletal disease (e.g., bone pain, osteopenia, bone infarct, osteonecrosis, pathological fractures), cytopenia (e.g., thrombocytopenia, anemia), fatigue, excessive bleeding, increased risk of infections, cardiovascular complications, and pulmonary disease. Enzyme replacement therapy (ERT) with recombinant glucocerebrosidase (imiglucerase, velaglucerase, or taliglucerase) is the current standard of care for symptomatic individuals with GD type 1. Sources: Expert list |
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| Additional findings_Adult v1.30 | FLCN |
Zornitza Stark gene: FLCN was added gene: FLCN was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: FLCN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: FLCN were set to Birt-Hogg-Dube syndrome (MIM#135150) Review for gene: FLCN was set to GREEN Added comment: BHDS is a rare condition characterized by renal tumors of varying histologic subtypes, cutaneous manifestations (cutaneous collagenomas and fibrofolliculomas, oral papules, and epidermal cysts), and pulmonary cysts (most often located in the basal lung regions), which can manifest as spontaneous pneumothoraces (with a clinical presentation ranging from asymptomatic to dyspnea and chest pain). Cutaneous perifollicular fibromas, acrochordons, and angiofibromas have also been associated with BHDS, but only fibrofolliculomas are specific for BHDS. Other findings reported in a small number of individuals includes thyroid nodules and cysts, thyroid cancer, colon polyps, colorectal cancer, parotid tumors, cutaneous-type oral papules, cutaneous melanomas, and various other tumor types. Initial screening for major clinical manifestations in individuals with BHDS includes screening for renal, lung and skin manifestations (including lung and pelvic CT). Referral to a cancer genetics professional should be considered. Sources: Expert list |
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| Additional findings_Adult v1.19 | CPS1 |
Zornitza Stark gene: CPS1 was added gene: CPS1 was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: CPS1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CPS1 were set to Carbamoylphosphate synthetase I deficiency MIM#237300 Review for gene: CPS1 was set to GREEN Added comment: Can rarely present in adulthood, including in the postpartum period with coma. ACMG factsheet relating to management of adults: https://www.acmg.net/PDFLibrary/CPS-I-Deficiency-Transition.pdf. Management aims to maintain stable metabolic control and to reduce or eliminate chronic complications. Treatment includes medications to promote waste nitrogen excretion (nitrogen scavengers such as sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, and glycerol phenylbutyrate); low-protein diet; and supplementation with arginine or citrulline, essential nutrients, and essential amino acids. Given the risk of acute metabolic decompensation during surgery and general anaesthesia, elective surgery should only be carried out in centers able and prepared to deal with hyperammonemic decompensations. Specialised management is also required during pregnancy. Steroids and valproate are to be avoided. Sources: Expert list |
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| Additional findings_Adult v1.11 | CDC73 |
Zornitza Stark gene: CDC73 was added gene: CDC73 was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: CDC73 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CDC73 were set to Hyperparathyroidism-jaw tumour syndrome, MIM# 145001; Hyperparathyroidism, familial primary, MIM# 145000 Review for gene: CDC73 was set to GREEN Added comment: CDC73-related conditions are considered as a spectrum that includes three phenotypes: HPRT2; hyperparathyroidism 1 (HPRT1; also known as familial isolated hyperparathyroidism or FIHP) and parathyroid carcinoma (PC). To establish the extent of disease and needs in an individual initially diagnosed with HRPT2, the following are recommended: •Evaluation for jaw tumors with panoramic jaw x-ray •Evaluation for renal lesions with ultrasound examination •Evaluation of standard skeletal and renal end organ damage of pHPT •Evaluation for uterine tumors with pelvic ultrasound examination, CT, or MRI (starting at reproductive age). Individuals newly diagnosed with any CDC73-related condition who have evidence of pHPT should be evaluated using a 24-hour urine calcium-to-creatinine clearance ratio. Hypercalcemic individuals (including asymptomatic) with pathogenic variants in CDC73 should be evaluated for pHPT (concomitant calcium and intact [i]PTH levels) and should be managed in consultation with an endocrinologist, with consideration given to referral to a high-volume parathyroid surgeon. Sources: Expert list |
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| Additional findings_Adult v0.153 | DES | Bryony Thompson Marked gene: DES as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.153 | DES | Bryony Thompson Gene: des has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.153 | DES | Bryony Thompson Classified gene: DES as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.153 | DES | Bryony Thompson Gene: des has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.152 | DES |
Bryony Thompson gene: DES was added gene: DES was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: DES was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DES were set to 35802134 Phenotypes for gene: DES were set to Cardiomyopathy, dilated, 1I, MIM# 604765; Myopathy, myofibrillar, 1 , MIM#601419 gene: DES was marked as current diagnostic |
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