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| Additional findings_Adult v1.74 | OAT |
Zornitza Stark gene: OAT was added gene: OAT was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: OAT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: OAT were set to Gyrate atrophy of choroid and retina with or without ornithinemia MIM#258870 Review for gene: OAT was set to GREEN Added comment: MODERATE actionability by ClinGen. The condition is characterized by the development of chorioretinal atrophic patches that start in the mid-peripheral retina in the first decade of life. Myopia, night blindness, changes in the macula (including cystic changes), and visual field affection usually start in the first or second decade. Most patients with GA have posterior subcapsular cataracts by the end of the second decade. Irreversible loss of vision and blindness generally occurs between 40 and 55 years of age but is highly variable. Treatment of GA consists mainly of dietary modifications to help lower elevated systemic ornithine levels. Restriction of dietary arginine, a precursor of ornithine, appears to have therapeutic value. Sources: Expert list |
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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 v1.38 | 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 v1.32 | HMBS |
Zornitza Stark gene: HMBS was added gene: HMBS was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: HMBS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: HMBS were set to Porphyria, acute intermittent, MIM#176000 Review for gene: HMBS was set to GREEN Added comment: AIP is characterized by intermittent and sometimes life-threatening acute neurovisceral attacks of severe pain, usually abdominal and generalized, without peritoneal signs. While all individuals with a pathogenic variant in HMBS are predisposed to acute attacks, most never have symptoms, and are said to have latent (or presymptomatic AIP). Attacks may be accompanied by nausea, vomiting, distention, constipation, diarrhea and ileus. Tachycardia, hypertension, and hyponatremia can occur, with fever, sweating, restlessness, and tremor occurring less frequently. Urinary retention, incontinence, and dysuria may be present. Neurologic findings may also occur including mental changes (e.g., insomnia, paranoia), convulsions, hallucinations, peripheral neuropathy (that may progress to respiratory paralysis), pain in extremities, paresis, weakness, and altered consciousness (from somnolence to coma). Seizures may occur in acute attacks, especially in individuals with hyponatremia. Attacks may be provoked by certain drugs, crash dieting, alcoholic beverages, smoking, endocrine factors, calorie restriction, stress, and infections or surgery which can increase the demand for hepatic heme. Attacks are usually due to the additive effects of several triggers, including some that are unknown. Individuals are usually well between attacks. Avoidance of precipitating factors and treatment of acute crises are the mainstays of clinical management. Sources: Expert list |
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| Additional findings_Adult v1.26 | CDKN1B |
Zornitza Stark gene: CDKN1B was added gene: CDKN1B was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: CDKN1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CDKN1B were set to Multiple endocrine neoplasia type 4, MEN4, OMIM #610755 Review for gene: CDKN1B was set to GREEN Added comment: MEN4 is a very rare hereditary cancer syndrome characterized by parathyroid adenoma/hyperplasia and pituitary adenomas (Cushing disease, prolactinoma, somatotroph, corticotroph, and nonfunctioning adenomas). Primary hyperparathyroidism (pHPT) as a uniglandular disease is the leading pathology. Less frequently, additional endocrine/neuroendocrine neoplasias have been reported, including gastroenteropancreatic neuroendocrine tumors (NETs) and Zollinger-Ellison syndrome, NETs of the cervix and lungs, papillary thyroid carcinoma, thymic tumors, and adrenal masses. Other reported rare manifestations include meningiomas, and cancers of the uterus, testes, breast, colon, and kidneys. Presymptomatic surveillance recommendations for MEN4 have been suggested and are as follows: •Annual blood tests recommended for pHPT (calcium) and biochemical surveillance for secretory pituitary somatotroph adenomas (annual IGF-1), beginning in adolescence. •Endocrine surveillance is primarily clinical and should concentrate on evidence of growth hormone excess (gigantism/acromegaly) and glucocorticoid excess (Cushing syndrome), with concern for either prompting endocrine consultation. 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 v0.160 | TTR |
Bryony Thompson gene: TTR was added gene: TTR was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: TTR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TTR were set to 35802134 Phenotypes for gene: TTR were set to Hereditary transthyretin-related amyloidosis MIM#105210 gene: TTR was marked as current diagnostic |
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| Additional findings_Adult v0.154 | RB1 |
Bryony Thompson gene: RB1 was added gene: RB1 was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: RB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RB1 were set to Retinoblastoma MONDO:0008380 gene: RB1 was marked as current diagnostic |
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| Additional findings_Adult v0.147 | RPE65 |
Zornitza Stark gene: RPE65 was added gene: RPE65 was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: RPE65 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: RPE65 were set to 34012068 Phenotypes for gene: RPE65 were set to RPE-related retinopathy Review for gene: RPE65 was set to GREEN Added comment: Included in ACMG V3.0 SF list, available gene therapy may be more effective earlier in disease. Sources: Expert list |
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| Additional findings_Adult v0.135 | TTN |
Zornitza Stark gene: TTN was added gene: TTN was added to Additional findings_Adult. Sources: Expert list Mode of inheritance for gene: TTN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TTN were set to 34012068 Phenotypes for gene: TTN were set to Cardiomyopathy, dilated, 1G, MIM# 604145 Review for gene: TTN was set to GREEN Added comment: Included in ACMG V3.0 SF list, risk fo sudden death with preventative interventions available. We note the difficulty in interpreting variants in this gene: truncating variants with previously established pathogenicity to be reported only. Sources: Expert list |
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| Additional findings_Adult v0.79 | RET | Zornitza Stark Marked gene: RET as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.79 | RET | Zornitza Stark Gene: ret has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.79 | RET | Zornitza Stark Phenotypes for gene: RET were changed from to Multiple endocrine neoplasia IIA, MIM# 171400; Multiple endocrine neoplasia IIB, MIM# 162300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.78 | RET | Zornitza Stark Mode of inheritance for gene: RET was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.77 | RET | Zornitza Stark reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple endocrine neoplasia IIA, MIM# 171400, Multiple endocrine neoplasia IIB, MIM# 162300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Additional findings_Adult v0.0 | RET |
Zornitza Stark gene: RET was added gene: RET was added to Adult additional findings_MelbGenomics. Sources: Expert Review Green,Melbourne Genomics Health Alliance Mode of inheritance for gene: RET was set to Unknown |
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