ACMG 100 Flashcards
22q11 deletion syndrome
Genes responsible: TBX1? UFDIL? (AD, de novo)
Clinical: heart disease (tetrology of fallot, conotruncal defect), immune dysfunction, palate issues, DD, ID, hypocalcemia, renal issues, psychiatric issues
Molecular tests: FISH or MLPA, microarray
Treatment: treat heart disease, palate repair, calcium supplement
Alagille Syndrome
Genes: JAG1, NOTCH2 (AD, 50-70% de novo)
Clinical features: bile duct paucity + any 3 of: heart defect (TOF), cholestasis, butterfly vertebrae, dysmorphic facies, DD, growth failure
Clinical tests: liver biopsy, bile duct paucity
Molecular tests: 88% JAG1 SNVs, 7% JAG1 del by FISH
Mechanism: LOF, truncated protein
Treatment: liver transplant, standard tx for cardiac, renal issues,
Brugada syndrome
Gene: SCN5A (AD)
Clinical features: Syncope, ST-segment abnormalities leading to high risk of arrhythmias and sudden death. Adult onset, but may present as SIDS
Clinical tests: ECG
Molecular tests: SCN5A seq
Mechanism: acceleration of inactivation of channel
treatment: defibrillators, isoproterenol; avoid inducing meds (vagotonic agents, adrenergic antagonists)
Hereditary Hemorrhagic telangiectasia
Gene: ACVRL1, ENG (AD)
Clinical features: nosebleeds, mucocutaneous telangiectasias, hemorrhage
clinical tests: stool for occult blood, CBC
Mechanism: LOF
Treatment: transcatheter embolizaiton of pulmonary AVM
Holt Oram syndrome
Gene: TBX5 (AD, de novo)
Clinical Features: carpal bone malformation (100%, very malformed thumb)), CHD, atrial/ventral septal defect, arrhythmia
Mechanism: TBX5 is a TF, mutants rapidly degraded or have decreased binding
Treatment: pacemaker, standard cardio care
LEOPARD syndrome
Genes: PTPN11, RAF1 (AD)
Clinical Features: Lentigenes (look for dark spots over skin), ECG anomalies, Ocular hypertelorism, Pulmonary stenosis, Abnormality of genetalia, Retardation of growth, Deafness (SNHL)
mechanism: LOF
Treatment: standard cardio/deafness treatements
Noonan syndrome
Genes: RAS pathway (PTPN11, SOS1, KRAS, RAF1, NRAS, CBL, SHOC2) (AD)
Clinical features: short stature, facial features, cardiomyopathy, pulmonary valve stenosis, renal malformation, bleeding dx, DD/ID
Molecular tests PTPN11 (50%), SOS1/RAF1 (10% each)
Mechanism: GOF (constitutive activation of RAS pathway)
Treamtnet: standard cardio care, GH replacement
Williams syndrome
Gene: 7q continuous gene del; ELN is critical (AD)
clinical features: arterial stenosis (aorta), facial features, joint laxity, ID, FTT
Clinical tests: creatinine, calcium
Molecular tests: FISH
Mechanism: LOF
Treatment: PT, OT; monitor cardio symptoms
Breast/Ovarian Cancer
Genes: BRCA1/2 (AD)
clinical features: breast, ovariant, prostate increased risk
clinical test: mammograms at 25, mastectomy/oopharectomy at 35
Molecular tests: full gene seq
Familial adenomatous polyposis
Gene: APC (AD)
Clinical features: colon polyps and cancer (100% lifetime risk), mean age is 39 yrs
Molecular tests: gene seq
Heriditary Nonpolyposis colon cancer
Genes: MLH1, MSH2, MLH6 (AD)
Clinical features: colon, endometrium, stomach, ovary cancers
Molecular tests: MLH1- seq (90-95%), MSH2 (50-69%)
treatment: 80% lifetime risk of colon cancer; colonoscopy every 1-2 yrs at age 20
Li-Fraumini
Gene: p53
Clinical features: tumors everywhere; bone, cartilage, soft tissue, breast, wilms tumor
Molecular tests: sequencing (95%)
Treatment: surveillance has not proven to help
Multiple endocrine neoplasia type1
Gene: MEN1
Clinical features: tumors in parathyroid, pancreas
Multiple endocrine neoplasia type2
Gene: RET
clinical features: thyroid, pheochromocytoma, parathyroid; mucosal neuromas on tongue/lips
mechanism GOF
treatment: thyroidectomy
Neurofibromatosis type 2
Gene: NF2
Clinical features: benign nerve tumors, cafe au lait macule, DD
molecular: seq (75%), del/dup (25%)
treatment: remove nerve tumors, death by 36
Cowden/proteus syndrome
Gene: PTEN
Clinical features: Cowden: mucocutaneous facial and oral papules, macrocephaly, gingival cobblestoning, high risk of breast, thyroid cancer
Proteus: overgrowth
Molecular tests: seq (80%), promoter variants (10%)
treatment: surveillance, derm, breast exams annually
Tuberous sclerosis
Gene: TSC1/2 (AD)
Clinical features- Derm: hypomelanotic macules. CNS-giant cell astrocytoma, seizures. Cardio- rhabdomyoma. Eye- hamartomas
treatment: renal screening
Von hippel lindau syndrome
Gene: VHL
Clinical features: hemangioblastoma (cerebellum, retina, spine), pheochromocytoma, renal cell carcinoma
treatment: annual eye exam at age 5, abdominal us at 15
Xeroderma pigmentosum
Gene: XPA, XPC, ERCC2 (AR)
Clinical features: sun sensitivity> severe keratitis and cognitive impairment. 1000x increased skin and eye cancer risk
Treatment; regular derm and eye exams, protection from UV
Aarskog syndrome
Gene: FGD1 (XR)
Clinical features: hypertelorism, brachydactyly, short stature, ID
Mechanism: unclear
Treatment: none
Antley-Bixler syndrome
Gene: POR (AR)
Clinical features: ambiguous genetalia, cystic ovaries, poor masculinization in males, craniosynostosis, choanal atresia, hydrocephalus, bowing of long bones, contractures
Mechanism: disorder of steroid and cholesterol synthesis due to cytochrome p450 reductase deficiency
Bardet-biedl syndrome
Gene: BBS1/10 (11 other genes too)
Clinical features: rod-cone dystrophy, obesity, polydactyly, ID, renal disease, genital malformations
Molecular tests: BBS1 M390R (20-32% of BBS) and C91fsx95 (10%)
mechanism: defective cilia
Brachiootorenal syndrome
Gene: EYA1, SIX1 (AD)
Clinical features: ear malformations w/ hearing loss, branchial fistulae, renal malformations
CHARGE syndrome
Gene: CHD7 (AD)
Clinical feature: eye coloboma, heart anomalies, choanal atresia, mental retardation, genitourinary malformations, ear malformations
mechanism: LOF
treatment: surgical correction of heart and GI issues
Coffin-Lowry synrome
Gene: RPS6KA3 (XD)
clinical features: profound ID, fleshy/small hands, short stature, microcephaly, facial dysmorphisms. Females=normal to profound ID
Cornelia de lange syndrome
Gene: NIPBL (AD), SMC1L1 (XR)
clinical features: postnatal growth retardation, synophrys, hernia, upper limb anomalies, moderate ID, VSD, pulmonary valve stenosis
