Syndromes Every Geneticist Should Know (ACMG) Flashcards
22q11 deletion (DiGeorge, Velocardiofacial syn, Schprintzen syn) CARDIO SYSTEM
genes: UFDIL, TBX1
locus: 22q11.2
AD; 93% de novo
features: CHD, immune dysfunction, palate abnormalities, feeding problems, DD, learning problems, hypocalcemia, renal anomalies, psychiatric disorders, medial deviation of the internal carotids
molecular tests: FISH
Alagille Syndrome CARDIO SYSTEM
genes: JAG1, NOTCH2 loci: 20p12, 1p13-p11
AD; 50-70% de novo
features: bile duct paucity (scarcity) on liver biopsy + any three of: cardiac defects, cholestasis, skeletal abnormalities (butterfly vertebrae), eye, or characteristic facial features (prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, saddle or straight nose with a bulbous tip). DD, growth failure
Molecular tests: JAG1 sequencing, FISH
Brugada Syndrome CARDIO SYSTEM
gene: SCN5A loci: 3p21
- Inheritance: AD
clinical features:
- syncope or nocturnal agonal respiration (gasping while asleep),
- ST-segment abnormalities on the ECG
- Manifests during adulthood,
- mean age of sudden death: 40 years
- May present as SIDS or sudden unexpected nocturnal death syndrome
- Molecular tests: SCN5A seq (20-25%)
Cardio-Facio-Cutaneous Syndrome CARDIO SYSTEM
- genes: BRAF, MEK1, MEK2, KRAS loci: 7q34, 15q22.31, 19p13.3, 12p12.1
- Inheritance: AD; majority de novo
- features: cardiac abnormalities, high forehead with bitemporal narrowing, posteriorly rotated ears with thick helices, hypertelorism with down slanting palpebral fissures, epicanthal folds and ptosis, depressed nasal bridge with anteverted nares (little pig noses per Bess), highly arched palate, cupids bow lips, cutaneous abnormalities (xerosis, hyperkeratosis, ichthyosis, eczema, ulerythema, ophyrogenes), mild-moderate ID
- Molecular test: gene seq
Costello Syndrome CARDIO SYSTEM
gene: HRAS loci: 11p15.5 AD; majority de novo features: feeding issues, DD, ID, coarse facial features, loose, soft skin, hypertrophic cardiomyopathy, pulmonary stenosis, arrhythmia, rhabdomyosarcoma; molecular tests: gene seq
Hereditary Hemorrhagic Telangiectasia CARDIO SYSTEM
genes: ACVRL1, ENG, SMAD4 loci: 12q11-q14, 9q34.1 AD features: nosebleeds (epistaxis), mucocutaneous telangiectases (lips, oral cavity, fingers, and nose), visceral AV malformation (pulmonary, cerebral, hepatic, spinal, GI) molecular test: seq and del/dup analysis
Holt-Oram Syndrome
gene: TBX5
loci: 12q24.1
AD; 85% de novo
features: malformation of carpal bone(s) and radial and/or thenar bones (left more severe than right). CHD, must often have multiple ASD or VSD, arrhythmia (even if no CHD)
molecular test: TBX5 sequencing (>70%) rarely del/dup
Noonan syndrome with multiple lentigines (LEOPARD) CARDIO SYSTEM
genes: PTPN11, RAF1 loci: 12q24, 3p25 AD features: lentigines (liver spots), eletrocardiographic conduction abn, ocular hypertelorism, pulmonary stenosis, abn of the genitalia, retardation of growth, deafness (sensorineural). Hypertrophic cardiomyopathy in majority. low-set ears. tests: sequencing
Noonan syndrome CARDIO SYSTEM
genes: PTPN11, SOS1, KRAS, RAF1, NRAS, CBL, SHOC2, BRAF loci: 12q24.1, 2p22-21, 12p12.1, 3p25, 1p13.2, 11q23.3, 10q25, 7q35 AD features: facial features, short stature, feeding problems, pulmonary valve stenosis, hypertrophic cardiomyopathy, cryptorchidism, renal malformation, lymphedema, bleeding disorders, myeloproliferative disorder, inc. risk of leukemia and learning disabilites tests: sequencing
“Male turner syndrome” - but affects males and females
Williams Syndrome
gene: ELN, contiguous gene del syndrome loci: 7q11.23 AD; majority de novo features: CV any artery may be narrowed, supravalvar aortic stenosis, facial features (broad brow, bi-temporal narowness, periorbital fullness, stellate/lacy iris pattern, strabismus, short nose, full nasal tip, malar hypoplasia, long philtrum, full ips, wide mouth, malocclusion, small jaw, prominent earlobes), hoarse voice, hernia, rectal prolapse, joint limitation or laxity, ID, friendly, anxiety, ADD, hypercalcemia, hypercalciuria, hypothyroid, FTT infancy tests: FISH & seq
Ataxia-Telangiectasia CHROMOSOME BREAKAGE DISORDER
- Gene: ATM
- Cytogenetic locus: 11q22.3
- Chromosomal breakage syndrome
- Inheritance: Autosomal recessive (carriers may be at risk for cancer)
- Clinical Features: Progressive cerebellar ataxia (onset age 1-4 years), oculomotor apraxia, conjunctival telangiectasia, immunodef, choreoathetosis, ionizing radiation sensitivity, risk of cancer (lymphoma and leukemia)
- Molecular tests: ATM sequencing (>95%). Amish founder mutation
Features: CHD, immune dysfunction, palate abnormalities, feeding problems, DD, learning problems, hypocalcemia, renal anomalies, psychiatric disorders, medial deviation of the internal carotids
22q11 deletion (DiGeorge, Velocardiofacial syn, Schprintzen syn) CARDIO SYSTEM
Mnemonic: CATCH-22
C: Cardiac defects
A: Abnormal facies
T: Thymic aplasia
C: Cleft palate
H: Hypocalecemia
22: on chromosome 22q11.2
features: bile duct paucity on liver biopsy + any three of: cardiac defects, cholestasis, skeletal abnormalities (butterfly vertebrae), eye, or characteristic facial features (prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, saddle or straight nose with a bulbous tip). DD, growth failure
Alagille Syndrome CARDIO SYSTEM
- Clinical features: syncope or nocturnal agonal respiration, ST-segment abnormalities on the ECG
- Manifests during adulthood, mean age of sudden death: 40 years
- May present as SIDS or sudden unexpected nocturnal death syndrome
Brugada Syndrome CARDIO SYSTEM
features: cardiac abnormalities, high forehead with bi-temporal constriction, posteriorly rotated hears with thick helices, hypertelorism with down slanting palpebral fissures, epicanthal folds and ptosis, depressed nasal bridge with anteverted nares, highly arched palate, cupids bow lips, cutaneous abnormalities (xerosis, hyperkeratosis, ichthyosis, eczema, ulerythema, ophyrogenes), mild-moderate ID
Cardio-Facio-Cutaneous Syndrome CARDIO SYSTEM
Heart
Face
Skin/Hair
features: feeding issues, DD, ID, coarse facial features, loose, soft skin, hypertrophic cardiomyopathy, pulmonary stenosis, arrhythmia
Costello Syndrome CARDIO SYSTEM
features: nosebleeds, mucocutaneous telangiectases (lips, oral cavity, fingers & nose), visceral AV malformation (pulmonary, cerebral, hepatic, spinal, GI)
Hereditary Hemorrhagic Telangiectasia CARDIO SYSTEM
Picture = mucocutaneous telangiectases
features: malformation of carpal bone(s) and radial and/or thenar bones (left more severe than right). CHD, most often have multiple ASD or VSD, arrhythmia (even if no CHD)
Holt-Oram Syndrome
Think: “HOLE’t-Oram”
“Holes” (aka; ASDs, VSDs)
features: lentigines, eletrocardiographic conduction abn, ocular hypertelorism, pulmonary stenosis, abn of the genitalia, retardation of growth, deafness (sensorineural). Hypertrophic cardiomyopathy in majority. low-set ears.
Noonan syndrome with multiple lentigines (LEOPARD) CARDIO SYSTEM
LEOPARD
L: Lentigines
E: Eletrocardiographic conduction abnormalities
O: Ocular hypertelorism
P: Pulmonary stenosis
A: Abnormalities of the genitalia
R: Retardation of growth
D: sensorineural Deafness
features: facial features, short stature, feeding problems, pulmonary valve stenosis, hypertrophic cardiomyopathy, cryptorchidism, renal malformation, lymphedema, bleeding disorders, myeloproliferative disorder, inc. risk of leukemia and learning disabilites
Noonan syndrome CARDIO SYSTEM
features: CV any artery may be narrowed, supravalvar aortic stenosis, facial features (broad brow, bi-temporal narowness, periorbital fullness, stellate/lacy iris pattern, strabismus, short nose, full nasal tip, malar hypoplasia, long philtrum, full ips, wide mouth, malocclusion, small jaw, prominent earlobes), hoarse voice, hernia, rectal prolapse, joint limitation or laxity, ID, friendly, anxiety, ADD, hypercalcemia, hypercalciuria, hypothyroid, FTT infancy
Williams Syndrome
W: Well developed verbal skills
I: Increased calcium
L: eLfin facies
L: eLastin gene microdeletion
I: Increased sensitivity to vitamin D
A: Aortic stenosis
M: Mental retardation
S: Stranger friendliness
- Clinical Features: Progressive cerebellar ataxia (onset age 1-4 yeasr), oculomotor apraxia, conjunctival telangiectasia, immunodef, choreoathetosis, ionizing radiation sensitivity, risk of cancer (lymphoma and leukemia)
Ataxia-Telangiectasia CHROMOSOME BREAKAGE DISORDER
Bloom Syndrome CHROMOSOME BREAKAGE DISORDERS
Gene: BLM
Locus: 15q26.1
Inheritance: Autosomal recessive (1/100 carrier frequency in AJ population)
Clinical Features and Diagnostic Criteria: IUGR, hyper and hypopigmentation, butterfly distribution sun sensitive telangiectasia, microcephaly, high pitched voice, normal intelligence, immunodeficiency, azoospermia, POF, increased risk of cancer (colon most common, but wide distribution of type and site)
Molecular Tests: BLM 2881 del6ins7 (97% mutant allele in AJ)
Clinical Features and Diagnostic Criteria: IUGR, hyper and hypopigmentation, butterfly distribution sun sensitive telangiectasia, microcephaly, high pitched voice, normal intelligence, immunodeficiency, azoospermia, POF, increased risk of cancer (colon most common, but wide distribution of type and site)
Bloom Syndrome CHROMOSOME BREAKAGE DISORDERS
Fanconi Anemia: CHROMOSOME BREAKAGE DISORDERS
- Responsible genes: 13 different fanconi anemia genes including BRCA2, PALB2, BRIP1, Others that start with “FANC”
- Inheritance: AR
- Clinical features and diagnostic criteria: short stature; abnormal pigmentation; radial, GU, ear, heart, GI, or CNS malformation; hearing loss, hypogonadism, developmental delay (DD). Progressive bone marrow failure, aplastic anemia, myelodysplastic syndrome, AML, solid tumor of head, neck, esophagus, cervix, vulva, or liver at unusually young age
- Molecular tests: Seq and del/dup analysis
- Clinical features and diagnostic criteria: short stature; abnormal pibmentation; radial, GU, ear, heart, GI, or CNS malformation; hearing loss, hypogonadism, developmental delay (DD). Progressive bone marrow failure, aplastic anemia, myelodysplastic syndrome, AML, solid tumor of head, neck, esophagus, cervix, vulva, or liver at unusually young age
Fanconi Anemia: CHROMOSOME BREAKAGE DISORDERS
Clinical features and diagnositic criteria: Marfanoid appearance, long slender fingers and toes, crumpled ears, major joint contracture, muscle hypoplasia, kyphosis/scoliosis, severe/lethal: aortic dilation, ASD, VSD, IAA, duodenal or esophageal atresia, malrotation
Congenital Contractural Arachnodactyly (Beals Syndrome) CONNECTIVE TISSUE DISORDER
Clinical features and diagnostic criteria: skin hyperextensibility, widened atrophic scars, joint hypermobility, smooth velvety skin, molluscoid pseudotumors (heaped up scar-like lesions over pressure points), subcutaneous spheroids (cyst-like lesions, feel like grains of rice, over bony prominences of legs and arms), joint sprains/dislocations/subluxations, hypotonia, easy bruising, hernia, chronic pain, aortic root dilation
Ehlers-Danlos Syndrome Classic Type (1 and 2)
CONNECTIVE TISSUE DISORDERS
Stickler syndrome
(Connective tissue disorder)
Genes: COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3
Phenotype: Severe myopia, cataracts, retinal detachment, hearing loss, conductive and sensorineural hearing loss, midface hypoplasia, cleft palate, short stature due to spondyloepiphyseal dysplasia, premature arthritis
Testing: gene sequencing and/or del/dup
Hypohidrotic Ectodermal Dysplasia (HED)
Genes: EDA, EDAR, EDARADD
X-linked (95%), AD or AR (5%)
Phenotype: Peeling skin at birth, perioral hyperpigmentation, hypotrichosis (sparse hair), hypohidrosis or anhydrosis (little-to-no sweating), hypodontia (5-7 teeth), conical shaped teeth, XL carriers may show mosaic pattern of hypohidrosis and hypodontia
Incontinentia Pigmenti
Gene: IKBKG
X-linked dominant (usually male lethal - fetuses miscarry)
Phenotype: Four stages of skin changes: erythema->blister->hyperpigmented streaks -> atrophic patches; hypo/andontia, small or malformed teeth, alopecia, woolly hair, nail ridging or pitting, retinal detachment, ID is rare, normal life expectancy
Testing: Southern blot for exon 4-10 deletion, skewed X inactivation in females
Clinical Features and Dx Criteria: Major involvement of 2 body systems and minor involvement of a 3rd.
Major Criteria: Cardiovascular - Dilation or dissection of the ascending aorta; Skeletal - Pectus carinatum or excavatum, reduced upper: lower segment or arm span: ht, scoliosis, pes planus, high palate, reduced elbow extension, protrusio acetabulae; Eye - ectopia lentis; Dura - lumbosacral dural ectasia; Family hx: pathogenic FBN1 mutation
Minor Criteria: Cardiovascular - MV, MR, dilation of main PA, mitral annulus calcification, dilation or dissection of the descending thoracic or abdominal aorta at age
Marfan Syndrome (CONNECTIVE TISSUE DISORDER)
Oculocutaneous Albinism
Genes: TYR (OCA1A, OCA1B), OCA2
Autosomal recessive
Phenotype: albinism, nystagmus, translucent iris, ocular abnormalities, vision problems, range of skin and eye pigmentation
Testing: TYR sequencing, OCA2 deletion testing
Severe myopia, cataracts, retinal detachment, hearing loss, conductive and sensorineural hearing loss, midface hypoplasia, cleft palate, short stature due to spondyloepiphyseal dysplasia, premature arthritis
Stickler syndrome
(Connective tissue disorder)
Peeling skin at birth, perioral hyperpigmentation, hypotrichosis (sparse hair), hypohidrosis or anhydrosis (little-to-no sweating), hypodontia (5-7 teeth), conical shaped teeth, XL carriers may show mosaic pattern of hypohidrosis and hypodontia
Hypohidrotic Ectodermal Dysplasia (HED)
Four stages of skin changes: erythema->blister->hyperpigmented streaks -> atrophic patches; hypo/andontia, small or malformed teeth, alopecia, woolly hair, nail ridging or pitting, retinal detachment, ID is rare, normal life expectancy
Incontinentia Pigmenti
Albinism, nystagmus, translucent iris, ocular abnormalities, vision problems, range of skin and eye pigmentation
Oculocutaneous Albinism
EDS Kyphoscoliotic Type (Type VI)
- Gene: PLOD1
- Autosomal Recessive
- Clinical Features and Dx Criteria: Major features: friable, hyperextensible skin, thin scars, easy bruising, generalized joint laxity, severe muscle hypotonia, progressive scoliosis, scleral fragility and rupture of the globe. Minor features: widened atrophic scars, marfanoid habitus, rupture of medium sized arteries, mild to moderate delay of attainment of gross motor milestones
- Molecular Tests: PLOD1 seq research only, unknown frequency
Clinical Features and Dx Criteria: Major features: friable, hyperextensible skin, thin scars, easy bruising, generalized joint laxity, severe muscle hypotonia, progressive scoliosis, scleral fragility and rupture of the globe. Minor features: widened atrophic scars, marfanoid habitus, rupture of medium sized arteries, mild to moderate delay of attainment of gross motor milestones
EDS Kyphoscoliotic Type (Type VI)
Kallman Syndrome Type 1 and 2 (ENDOCRINE SYSTEM)
- Genes: KAL, FGFR1
- X-linked recessive or autosomal dominant
- Type 1 AND 2 features: hypogonadotropic hypogonadism and anosmia (no sense of smell). Usually present with delayed pubertal development
- Type 1: can also include mirror hand movements, ataxia, GU anomaly, high palate, pes cavus
- Type 2: ID, CL/P cryptorchidism, choanal atresia, CHD, sensorineural hearing loss
- Molecular Tests: Sequencing KAL (5-10%), FGFR1 (8-16%)
Type 1 AND 2 features: hypogonadotropic hypogonadism and anosmia (no sense of smell). Usually present with delayed pubertal development
Type 1: can also include mirror hand movements, ataxia, GU anomaly, high palate, pes cavus
Type 2: ID, CL/P cryptorchidism, choanal atresia, CHD, sensorineural hearing loss
Kallman Syndrome Type 1 and 2 (ENDOCRINE SYSTEM)
Klinefelter Syndrome (ENDOCRINE SYSTEM)
47, XXY
Clinical features: tall stature, slightly delayed motor and language skills, increased learning problems, testosterone plateaus age 14, small fibrosed testes, azoospermia and infertility, gynecomastia, increased cholesterol, slightly increased risk of autoimmune disorders and mediastinal germ cell tumors (1% risk)
Disease Mechanism: 1st or 2nd meiotic division nondisjunction of either parent. Maternal>paternal origin + AMA effect
Clinical features: tall stature, slightly delayed motor and language skills, increased learning problems, testosterone plateaus age 14, small fibrosed testes, azoospermia and infertility, gynecomastia, increased cholesterol, slightly increased risk of autoimmune disorders and mediastinal germ cell tumors (1% risk)
Klinefelter Syndrome (ENDOCRINE SYSTEM)
McCune-Albright Syndrome (ENDOCRINE SYSTEM)
- Gene: GNAS
- Sporadic Inheritance
- Clinical Features: polyostotic fibrous dysplasia, pathologic fracture, cranial foramina thickening -> deafness and blindness, large irregular cafe au lait (“coast of Maine”), precocious puberty, hyperthyroidism, increased GH, PRL, or PTH, ovary cysts
- Clinical Tests: x-ray, pelvic U/S, vision and hearing tests, pituitary hormone analysis
- Molecular tests: targeted mutation analysis
- Clinical Features: polyostotic fibrous dysplasia, pathologic fracture, cranial foramina thickening -> deafness and blindness, large irregular cafe au lait (“coast of Maine”), precocious puberty, hyperthyroidism, increased GH, PRL, or PTH, ovary cysts
McCune-Albright Syndrome (ENDOCRINE SYSTEM)
