100 Genetic Syndromes

Front 1

ACUTE INTERMITTENT PORPHYRIA

Back 1

Responsible gene: HMBS Protein: Porphobilinogen deaminase

Inheritance: AD

Clinical Features and Diagnostic Criteria: Onset after puberty, acute attacks, abdominal pain, muscle weakness, neuropathy, hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS
FINDINGS

Molecular Tests: HMBS gene sequencing (>98%)

Disease Mechanism: ?direct neurotoxicity of PBG, ?generation of reactive oxygen species or inhibition of GABA release at central synapses by ALA, ?loss of heme in the CNS

Treatment: Stop or treat precipitant (medication, infection, EtOH, dehydration, smoking, poor caloric intake); intubate if bulbar paralysis; pain control

Front 2

ALPHA THALASSEMIA

Back 2

Responsible genes: HBA1, HBA2

Inheritance: AR; if parents Alpha Thal trait, risk for HbH disease if one parent’s mutations are in cis, at risk for HB Bart if both parents in cis

Clinical Features and Diagnostic Criteria: HB Bart: loss or dysfunction of all 4 alpha thal alleles, hydrops fetalis, death in neonatal period; HbH: loss or dysfunction of 3 of 4 alpha thal alleles, microcytic hypochromic hemolytic anemia, HSM, jaundice Alpha Trait:loss or dysfunction of 2 alpha thal alleles, low MCV, low MCH, nl levels Hgb A2 and F; Alpha “silent” carrier: loss or dysfunction of one alpha thal allele, none or mild thalassemia-like effect

Clinical Tests: MCV, MCH, peripheral smear, reticulocyte count, hemoglobin electrophoresis. Prenatal screen at risk populations!
Molecular Tests: Targeted mutation analysis for common deletions (90%); gene sequencing (10%)
Disease Mechanism: Inability to form normal HbA

Front 3

BETA-THALASSEMIA

Back 3

Responsible gene: HBB

Inheritance: AR

Clinical Features and Diagnostic Criteria: severe anemia and HSM. Without Tx: severe FTT and shortened life expectancy. Thal. intermedia: present later, milder anemia, only rarely requires transfusion; at risk for iron overload due to inc intestinal absorption of iron. The clinical severity of the beta-thal syndromes depends on the extent of globin alpha chain/non-globin alpha chain imbalance.

Carriers: reduced MCV, MCH, and RBC morphologic changes that are less severe than in affected individuals.

Molecular Tests: Mutation scanning/sequencing. In each at-risk population, 4-10 mutations account for the large majority of HBB disease.

Front 4

FACTOR V
LEIDEN THROMBOPHILIA

Back 4

Responsible gene: F5

Inheritance: AD (moderately inc risk VTE), AR (significantly inc risk VTE)
Clinical Features and Diagnostic Criteria: inc risk venous thromboembolism (VTE), most commonly deep venous thrombosis (DVT). Heterozygous: at most
modest inc in VTE recurrence risk, 2-3x inc RR pregnancy loss. Homozygous: Inc chance VTE recurrence. Arterial thrombosis, MI, and stroke not associated with factor V Leiden.

Molecular Tests: F5 G to A substitution at nt 1691 (100%)

Disease Mechanism: The G>A substitution affects an APC cleavage site and the mutant factor V Leiden is inactivated 10x more slowly and persists longer in
circulation-> inc thrombin generation

Treatment/Prognosis: Risk of VTE compounded by coexisting thromboembolic d/o, malignancy, travel, central venous catheters, pregnancy, OCP, HRT, advancing age, surgery, organ transplant. Long-term heparin

Front 5

HEMOPHILIA A

Back 5

Responsible gene: F8

Protein: Coagulation Factor VIII

Inheritance: XLR

Clinical Features and Diagnostic Criteria: hemarthrosis or intracranial bleed with mildno trauma; deep muscle hematomas; prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising.

Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-35% Factor VIII activity. 10% of carrier females have Factor VIII activity <35%.

Molecular Tests: Severe: F8 intron 22-A gene inversion (45%), F8 intron 1 gene inversion (3%), F8 gene del or rearrangement, frameshift, splice junction, or nonsense mutations (40%), missense mutation (10%). Mildmoderate: missense mutation (97%)

Disease Mechanism: Normal Factor VIII circulates as an inactivated clotting cofactor activated by thrombin. Severe mutations lead to absent protein, mild-mod mutations to abnormal protein.
Treatment/Prognosis: IV Factor VIII

Front 6

HEMOPHILIA B

Back 6

Responsible gene: F9

Clinical Features and Diagnostic Criteria: hemarthrosis or intracranial bleed with mild or no trauma; deep muscle hematomas; prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising.

Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-30% Factor IX activity. 10% of carrier females have Factor VIII activity <30%.

Molecular Tests: F9 sequence analysis (99%). Large gene deletions, nonsense mutations, and most frameshift mutations cause severe disease.

Disease Mechanism: Factor IX activates Factor X which is a critical early step that can regulate the overall rate of thrombin generation in coagulation.

Treatment/Prognosis: Recombinant factor IX concentrate 2-3x/wk for severe deficiency and within one hour of trauma. Consider HIV, Hep A, B, and C testing if history of receiving blood
products.

Front 7

HFE-ASSOCIATED HEREDITARY
HEMOCHROMATOSIS (HFE-HHC)

Back 7

Responsible gene: HFE

Inheritance: AR (penetrance is low, a large fraction of homozygotes never develop symptoms).

Clinical Features and Diagnostic Criteria: Inappropriately high iron absorption by GI mucosa leads to excessive iron storage in the liver, skin,
pancreas, heart, joints, testes. Early Sx: abdominal pain, weakness, lethargy, weight loss.

Molecular Tests: Targeted mutation testing (60-90% C282Y/C282Y; 3-8% C282Y/H63D.

Disease Mechanism: HFE protein binds transferrin receptor 1 and is thought to reduce cellular iron uptake- mutation leads to inc iron uptake

Treatment/Prognosis: If untreated: hepatic fibrosis or cirrhosis, increased skin pigmentation, DM, CHF and/or arrhythmias, cardiomyopathy, arthritis, or hypogonadism. Treat with phlebotomy if symptomatic, aim for ferritin <50, transferrin-iron saturation <50%

Front 8

22q11 DELETION SYNDROME
(DiGeorge, Velocardiofacial syndrome, Shprintzen syndrome)

Back 8

Responsible genes: ?UFDIL,

Inheritance: AD; 93% de novo

Clinical Features and Diagnostic Criteria: congenital heart disease (74%) (TOF, IAA B, conotruncal defects), immune dysfunction, palate abnormalities (69%), feeding problems, developmental delay, learning
problems (70-90%), hypocalcemia (50%), renal anomalies (37%), psychiatric disorders, medial deviation of the internal carotids

Molecular Tests: FISH or MLPA for DGCR deletion (95%). 3-Mb or 20-kb deletion; no clear genotype-phenotype relationship to del size. (A small % with S/Sx 22q11 del without a DGCR deletion have 10p13-
p14 deletion)

Disease Mechanism: Abnormal development of the pharyngeal arches somehow related (at least in part) to TBX1 dosage

Treatment/Prognosis: Standard Tx for congen heart dz, palate repair, pharyngeal flap, Ca replacement, no live vaccines if immunodeficient

Front 9

ALAGILLE SYNDROME

Back 9

Responsible genes: JAG1, NOTCH2

Inheritance: AD, 50-70% de novo

Clinical Features and Diagnostic Criteria: Dx: Bile duct paucity on liver bx + any three of: cardiac defects (most often PA disease, TOF), cholestasis, skeletal abnormalities (butterfly vertebrae), eye (posterior
embryotoxin, or characteristic facial features. Also developmental delay, growth failure

Molecular Tests: seq JAG1 (88%), JAG1 20p12 del FISH (~7%), NOTCH2 seq (<1%)

Disease Mechanism: JAG1:Truncated protein product rendering it unable to bind to the cell membrane resulting in functional haploinsufficiency

Treatment/Prognosis: Liver transplant, cardiac and renal anomalies treated in standard manner, evaluate head injuries and CNS symptoms for vascular accidents, fat soluble vitamins, monitor growth and development

Front 10

BRUGADA SYNDROME

Back 10

Responsible gene: SCN5A

Inheritance: AD

Clinical Features and Diagnostic Criteria: Syncope or nocturnal agonal respiration. ST-segment abnormalities in leads V1-V3 on the ECG and a high risk of ventricular arrhythmias and sudden death. Manifests primarily during adulthood (range 2 days to 85 yrs). Mean age of sudden death: 40 yrs. May present as SIDS or the sudden unexpected nocturnal death syndrome (a typical presentation in individuals from Southeast Asia). May have FH sudden cardiac death.

Clinical Tests: ECG

Molecular Tests: SCN5A scanning/seq (20-25%)

Disease Mechanism: Gene mutations cause lack of expression of or acceleration in the inactivation of cardiac sodium channels.

Treatment/Prognosis: Implantable defibrillators, isoproterenol, avoid inducing medication (vagotonic agents, alpha adrenergic antagonists, beta adrenergic antagonists, TCA, first generation antihistamines, cocaine, class 1C antiarrhythmic drugs, class 1A agents (procainamide, disopyramide)

Front 11

HEREDITARY HEMORRHAGIC
TELANGIECTASIA

Back 11

Responsible genes: ACVRL1, ENG

Inheritance: AD

Clinical Features and Diagnostic Criteria: nosebleeds, mucocutaneous telangiectases (lips, oral cavity, fingers, and nose), visceral AV malformation (pulmonary, cerebral, hepatic, spinal, gastrointestinal). Hemorrhage is often the presenting symptom of cerebral AVM. Most visceral AVM’s present as a result of blood shunting through the abnormalvessel and bypassing the capillary beds.

Molecular Tests: Sequence analysis ACVRL1, ENG (60-80%), duplication/deletion analysis (10%)

Disease Mechanism: HHT is assumed to be the result of haploinsifficiency

Treatment/Prognosis: Transcatherter embolization of pulmonary AVM >3.0mm. OCP can decrease/eliminate bleeding. Liver transplant if hepatic AVM is causing heart failure.

Front 12

HOLT-ORAM SYNDROME

Back 12

Responsible gene: TBX5

Inheritance: AD (85% de novo)

Clinical Features and Diagnostic Criteria: Malformation of the carpal bone(s) and, variably, the radial and/or thenar bones (left often more severe than right). 100% have carpal bone abnormality. 75% have CHD, most often multiple ASD or VSD, arrhythmia including AV block (even if no CHD)

Clinical Tests: hand xray

Molecular Tests: TBX5 sequencing (>70%), Del/Dupl analysis (<1%)

Disease Mechanism: The TBX5 protein product is a transcription factor with an important role in both cardiogenesis and limb development. TBX5 mutations lead to mutant TBX5 mRNAs that are
rapidly degraded or to transcripts with diminished DNA binding- both of which result in decreased gene dosage.

Treatment/Prognosis: Pacemaker if severe heart block, standard cardiac surgery, pollicization may be indicated if thumb aplasia/hypoplasia. Annual ECG, annual Holter if h/o abnormal ECG