www.meddean.luc.edu lumen meded usmle table of genetic disorders

7/22/2019 Www.meddean.luc.Edu Lumen MedEd USMLE Table of Genetic Disorders

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Table of Genetic Disorders

Disease Gene/Defect Inheritance Clinical Features

Achondroplasia Fibroblast growthfactor receptor 3(FGR3) constitutively active(gain of function)

Autosomaldominant (normalparents can have an

affected child due to newmutation, and risk ofrecurrence in subsequentchildren is low)

Short limbs relative to trunk, prominentforehead, low nasal root, redundantskin folds on arms and legs

Cystic Fibrosis Cystic fibrosistransmembraneregulator (CFTR) impaired chlorideion channel function

AutosomalRecessive (mostcommon genetic disorderamong Caucasians inNorth America)

Pancreatic insufficiency due to fibroticlesions, obstruction of lungs due tothick mucus, lung infections (Staph,aureus, Pseud. aeruginosa)

Duchenne MuscularDystrophy

Dystrophin (DMD) -deletions

X-linked recessive Gradual degeneration of skeletalmuscle, impaired heart and respiratorymusculature

Hypercholesterolemia LDL receptor

(commonly)

Autosomal

dominant(haploinsufficiency)

Impaired uptake of LDL, elevated levels

of LDL cholesterol, cardiovasculardisease and stroke. Symptoms moresevere in homozygous individuals

Fragile X Syndrome (FMR1) CGGtrinucleotide repeatexpansion in 5untranslated regionof the gene(expansion occursexclusively in the mother)

X-linked dominant(females less severelyaffected)

Inheritancecharacterized byanticipation

Disorder shows anticipation (femaletransmitters in succeeding generations produce

increasing numbers of affected males) Boyswith syndrome have long faces,prominent jaws, large ears, and arelikely to be mentally retarded.

Gauchers Disease -Glucosidase Autosomal recessive Lysosomal storage diseasecharacterized bysplenomegaly,hepatomegaly, and bone

marrow infiltration. Neurologicalsymptoms are not common

Glucose 6-phosphatedehydrogenasedeficiency

Glucose 6-phosphatedehydrogenase

X-linked recessive(prominent amongindividuals ofMediterranean and

African descent)

Anemia (due to increased hemolysis)induced by oxidizing drugs,sulfonamide antibiotics, sulfones (e.g.dapsone), and certain foods (e.g. fava

beans)

Hemochromatosis Unknown gene onthe short arm ofchromosome 6

Autosomal recessive(Incidence ~0.3% inCaucasoid population.Women less affected dueto increased iron lossthrough menstruation)

Enhanced absorption of dietary ironwith accumulation of abnormal,pigmented, iron-protein aggregates(hemosiderin) in visceral organs.Cirrhosis, cardiomyopathy, diabetes,skin pigmentation, and arthritis.

Holoproencephaly Sonic Hedgehog(SHH)

Autosomaldominant(haploinsufficiency?)

Malformation of the brain (no or reducedevidence of an interhemispheric fissure),dysmorphic facial features, mentalretardation

Huntington Disease(Also HuntingtonChorea)

Huntingtin (HD) CAG repeatexpansion withinexon 1 (expansionoccurs in father)

Autosomaldominant (gain-of-function mutation)Shows anticipaton

Disorder is characterized by progressivemotor, cognitive and psychiatricabnormalities. Chorea nonrepetitiveinvoluntary jerks is observed in 90%of patients


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Klinefelter Syndrome 47,XXY males 50% of cases dueto errors in paternalmeiosis I

Sterile males with long limbs, smallgenitalia, breast development, andfeminine body contours, and learningdisabilities

Marfan Syndrome Fibrillin-1 gene(FBN1) encodes a

microfibril-formingconnective tissueprotein

Autosomaldominant (dominant

negative effect)

Abnormalities of the skeleton(disproportionate tall stature, scoliosis),

heart (mitral valve prolapse, aorticdilatation, dissection of the ascendingaorta), pulmonary system, skin(excessive elasticity), and joints(hypermobility). A frequent cause ofdeath is congestive heart failure.

Myoclonic Epilepsywith Ragged RedFibers (MERRF)

Mitochondrial DNAmutation in thetRNAlysgene

Maternaltransmission,heteroplasty

Age of onset varies depending onfraction of mutant mitochondrial DNAinherited. Symptoms include myopathy(disease takes its name from abnormalhistological appearance of skeletal muscle

biopsies), dementia, myoclonic seizures,ataxia, and deafness

Myotonic Dystrophy A protein kinasegene (DMPK) CTGrepeat expansion in3 untranslatedregion of the gene

AutosomaldominantShows anticipation

Disorder shows anticipation. Muscleweakness, cardiac arrhythmias,cataracts and testicular atrophy inmales. Children born with congenitalform have a characteristic opentriangle-shaped mouth

Neurofibromatosis I Microdeletion at17q11.2 involvingthe NF1gene

Autosomaldominant

The disorder is characterized bynumerous benign tumors(neurofibromas) of the peripheralnervous system, but a minority ofpatients also show increased incidenceof malignancy (neurofibrosarcoma,astrocytoma, Schwann cell cancers and

childhood CML chronic myelogenousleukemia)

OsteogenesisImperfecta

Either of the genesencoding the 1 or2 chains of type Icollagen

Usually autosomaldominant(null mutations result inhaploinsufficiency,missense mutations oftenproduce a dominantnegative effect

Null mutations produce a milder formof the disease. Missense mutationsthat act in a dominant negative mannerare often perinatal lethal. Thedisorders are associated withdeformed, undermineralized bones thatare subject to frequent fracture.

Phenylketonuria Usually due to amutation inPhenylananine

hydroxylase (PAH)

Autosomal recessive Mental retardation, if untreated,possibly due to inhibition of myelinationand disruption of neurotransmitter

synthesis. Detectable by newbornscreening and treatable

Polycystic KidneyDisease

Mutations in eitherpolycystin-1 (PKD1)or polycystin-2(PKD2) gene

Autosomaldominant (diseaseappears to follow a two-hit model, requiring theloss of both alleles ofPDK1 or PDK2 for thedisease to be evident.

Heterozygous individuals arepredisposed to polycystic kidneydisease because they are likely toloose the second good copy of thegene during their lifetime. Multiple

renal cysts, blood in urine, end-stagerenal disease and kidney failure.


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Prader Willi/Angelman(PWS/AS)

Deletion of the PWSregion and AS genelocated at 15q11-q13. Can also becaused by uniparentaldisomy involvingchromosome 15

ComplexParent of origineffects due togenomic imprinting.

Inheriting the deletion through themother gives rise to Angelmansyndrome, which is characterized byshort stature, severe mentalretardation, spasticity, seizures, and acharacteristic stance. Inheriting the

deletion from the father produces themore common Pader-Willi syndrome,which is characterized by obesity,

excessive and indiscriminate gorging,small hands, feet, hypogonadism andmental retardation. In rare cases,uniparental disomy involving chromosome 15produces PWS when both copies are inheritedfrom the mother and AS when both copies areinherited from the father.

Sex Reversal Variety of causes Various See Thompson & Thompson, MedicalGenetics, 6th ed.

Tay-Sachs Disease -Hexosaminidase(A isoenzyme(HEXA)

Autosomal recessive(common among Jew of

Eastern Europeanancestry and FrenchCanadians).

Hypotonia, spasticity, seizures,blindness, death by age 2. An earlyindication is a cherry red spot on theretina. (Incidence greatly reduced byscreening)

Thalasemias AutosomalRecessive

Severe anemia

Turner Syndrome 45,X females Usually due to a

paternal error in sexchromosometransmission

Although usually lethal in utero, the

defect poses little risk to survival ininfants that do come to term. Shortstature, webbed necks, broad chestwith widely spaced nipples, andsterility. Infants show evidence oflymphedema in fetal life. Intelligence is

normal.Xerodermapigmentosum

Anyone of ninegenes involved innucleotide excisionrepair (locusheterogeneity)

Autosomal recessivecharacterized byvariableexpressivity, andgeneticheterogeneity

Acute photosensitivity, premature skinaging, premalignant actinic keratoses,and benign and malignant neoplasmsof the skin, including basal cellcarcinoma, squamous cell carcinoma,or both. 5% of patients developmelanomas. Patients also exhibitocular problems due to UV damage and

have a 10- to 20-fold increasedincidence of internal neoplasms due toan inability to repair DNA damage byendogenously generated and

environmental genotoxic agents.

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