Inheritance and Risk of Genetic Disorders

Everything my GC school profs may want me to know about specific genetic disorders

Cystic Fibrosis

• mendellian, autosomal recessive

• pleiotropy → a single gene mutation affects mucus glands throughout the body, caysung seemingly unrelated effects

• Allelic Heterogeneity → multiple different mutations of the same gene will produce the same condition

Sickle Cell

• Mendelian - autosomal recessive

• only one specific mutation of a single gene causes the characteristic mishapen red blood cells, and the resulting lower blood supply + oxygen transport

• heterozygous advantage → heterozygotes often have less severe manifestations, and carry some malaria resistance, so the disorder has become more promenant in people with ancestry from high malaria risk places, like Africa

Hemophilia

• x linked recessive

• Can cause severe bruising and bleeding 

• Locus heterogeneity → multiple single gene forms-two people with the same diagnosis could have mutations at two entirely different genes

• Allelic Heterogeneity→ multiple different mutations of the same gene will produce the same condition

Polydactyly

• autosomal dominate

• variable expressivity - a characteristic extra digit can appear on only one hand, both hands, a hand and a foot, etc.

• incomplete penetrance → can appear to skip a generation despite not being recessive

• Locus heterogeneity → multiple single gene forms-two people with the same diagnosis could have mutations at two entirely different genes

Duchenne Muscular Dystrophy

• x linked recessive and fatal - mostly males experiencing selective pressure

• 10% of isolated cases are due to maternal germ line mosaicism, and 1/3 from de novo mutations

• causes progresive muscle weakness

• Caused by a premature stop codon that creates transcription factors for miRNA’s that silence the dystrophin gene, and promote inflammatory cytokines to break down the muscle

• Exon skipping therapy → makes the mutation in-frame, removes the premature stop codon, and reduces severity

Marfan Syndrome

• autosomal dominate

• connective tissue disorder → causes tall and slim habitus, cardiac problems

Tay Sachs

• autosomal recessive

• lysosomal storage disorder → b-HEXA enzyme is unable to break down GM2 sphingolipid

• progressive muscle weakness, neurodegeneration, cherry red spots on eyes

• Founder Effect → highly prominent among Akazaki jews in North America, due to a migration skewing the allele frequency among their population

• NOT included in newborn screening because only effective treatment is enzyme replacement therapy 

• Pseudodefficiency alleles make sequencing a necessary part of diagnosis 

Rhett’s Disease

• x linked dominate

• Neurodevelopmental disorder

• Lethal in males → thus 99% of cases are from de novo mutations

Achondroplasia

• Autosomal dominate

• most common cause of severe short stature, due to an underdeveloped skeletal system

• 7/8 cases are de novo mutations

• BUT mating within the “dwarf” community has increased the prevalence of the fatal homozygous genotype, due to nonrandom mating

Fragile X

• x-linked trinucleotide repeat expansion

• Expansions typically onl;y happen in maternal line

• Most common single-gene cause of inherited intellectual disability and autism

• Comes with distinctive physical features-long face w/ broad forehead, large low-set ears,, etc.

• Large range of expansions that are not fully diseased, but carry premiutations that could cause neurodegeneration/ataxia in males (FXTAS) or ovarian insufficiency in females (FXPOI)

Huntington’s Disease

• fatal neurodegenerative disorder

• Polyglutamine (CAG repeat on a coding exon region) trinucleotide repeat expansion

• Largely dominate inheritance pattern with complete penetrance, and expansions only happening in the paternal line

• Longer trinucleotide expansions lead to earlier age of onset and more severe presentation

MELAS

• Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes

• Disorder stemming from Mitochondrial DNA - can only be maternally inherited

• Common features - recurring stroke episodes, seizures, migranes, and/or dementia from an early age (<40).

MERRF

• Myoclonic Epilepsy with Ragged Red Fibers

• Disorder stemming from Mitochondrial DNA - can only be maternally inherited

• Common features- ataxia (uncoordinated, uncontrolled muscle movements), seizures (epilepsy), irregularly-shaped red muscle fibers

Albinism

• * Autosomal Recessive

• Light pigmentation and poor eyesight

Neurofibromatosis

• Autosomal Dominate

• Cafe-au-lait spots, neurofibroma or and/or optic glioma tumors → variable expressivity

• Alleluia heterogeneity → can have a single gene cause

PKU

• Disruption of PAH enzyme, which converts the → tyr,  or its cofactor BH4

• Aminoacidopathy → buildup of toxic amino acid (phe) and decrease in an amino acid usually not found in diet (tyr)

• Intellectual and behavioral differences, seizures/parkinson’s-like features, decreased pigmntation (Tyr is involved in melanin production)

• Detectd in newborn screening, followed by sequencing the PAH gene or looking at Phe:Tyr ratio in plasma amino acids

• Treated withspecialized diet, palynziq enzyme substitution, 

Galactosemia

• Disruption of GALT enzyme in glucose metabolism

• Buildup of toxic Gal-1-p

• Detected in newborn screening followed by GALT enzyme (low) or galactose (high) analysis

• Dietary intervention must be started within a few days of birth

OTC Deficiency

• Only x-linked urea cycle disorder

• Ammonia accumulation

• Problems revolving around feeding struggles (vomiting, lethargylow body temp)

• Can be treated by cleaning ammonia out of the blood w/ dialysis, liver transplant, or nitrogen scavenger drugs (Ammonul) that push the excess ammonia into being used in secondary pathways

Gaucher Disease

• Lysosomal storage disorder affecting breakdown of toxic glucocerebroside (GL-1)

• NOT in most newborn screens

• Symptoms include enlarged spleen/liver, bone pain and deformaties, cytopenias (blood cell deficiencies)

• Detected by testing GBA enzyme (low) or b-glucocerebroside (high)  activity

• Treatment → cerezyme enzyme replacement therapy

Alkaptonuria

• Aminoacidopathy → HGD enzyme cannot breakdown homogenistic acid as part of Tyr degredation pathway

• HGA forms cartilage-binding pigments in urine and connective tissue tissue → dark colorations

• NOT in newborn screening → detected using urine samples

MPS1

• lysosomal storage disorder → disruption of IDUA enzyme, and resulting accumulation of GAG’s, increases size of lysosome

• multisystemic → symptoms include ID, flat/wide facial features, corneal clouding, macrocephaly/hepatosplenomegaly

• Detectd in newborn screening followed by gene sequencing or IDUA (low)/GAG (high) activity

• Treatments include bone marrow transplants to introduce more healthy stem cells, or aldurazyme enzyme replacement therapy

Biotinidase Deficiency

• due to defective recycling of biotinidase, which is important for carboxylase enzyme function

• often associated with alopecia, low muscle tone (hypotonia), ataxia, hearing and vision problems

• Detected by newborn screening/sequencing followed by BTD enzyme measurment (low)

cystinuria

• transport defect → a transporter protein in kidneys causes amino acids to not be reabsorbed from urine

• concentration of amino acids created crystals that can cause UTI ‘s and kidney/bladder stones

• Detected via urine sample

Homocystinuria

• defect in CBS enzyme prevents breakdown of methionine to cystine

• potential for CNS problems (ID, seizures) and marfan habitus (tall and slender features)

• Detected via newborn screening followed by checking plasma amino acids for increased meth and homocysteine

• supplementation with either vitamin B6 or B12 + folate, or promoting alternate methylation with betain therapy, will reduce homocystine levels by turning them back to methionine, but will not lower elevated methionine levels

Carnatine deficiency

• Transport defect → disruption of OCTN2 gene means carnitine proteins will not be brought into cells to transport fatty acids into the mitochondria for metabolism, or remove toxic free carbon chains

• often associated with myopathy (muscle weakness)

• detected in newborn screening followed by reduced carnatine and acylcarnatine profiles

familial hypercholesterolemia

• receptor defect → either prevents the LDL receptor itself from working, prevents it from recycling itself and popping back out of the cell’s surface after sinking down with an LDL, or be a defect in toe APOB protein needed for LDL’s to bind to the receptor

• LDL’s are sticky → if not taken up and processed by cells, can build up under artery walls and crate blockages → heart disease

• Statin drugs can block cholesterol synthesis, Ezetimibe decreases absorption of cholesterol from food, bile acid sequesterants simulate liver to use excessive cholesterol to make bile → all limit the body’s cholesterol supply to what’s already in the blood

Fabray

• only x-linked lysosomal storage disorder → defect in GLA enzyme causes increase in GL3 sphingolipids

• major symptoms → heat intolerance from an inability to sweat, and prickling/burning sensation in the hands and feet, and increased risk for kidney/heart disease

• Treatments include fabrazyme enzyme replacement, or sometimes a kidney transplant

Prader-Willi

• Imprinting disorder → missing expression from a gene only active on paternal chromosome 15, either through an interstitial deletion (two breaks fused together) of the imprinting control region or uniparental disomy

• Major symptom is compulsive eating/obesity

Angelmann

• imprinting disorder → missing expression of a gene oinly active on maternal chromosome 15, either due to interstitial deletion (two breaks) of the imprinting control region, or uniparental disomy

• major symptom → frequent happy/excitable demeanor

Spinal Muscular Atrophy

• Caused by missing SN1 gene

• First personalized RNA therapy treatment → prevents truncation of SN2 protein via alternate splicing so it can compensate for the missing SN!

Hutchinson-Gilford Progeria syndrome

• Premature aging disorder resulting from a defect in alternative splicing

Down Syndrome

• Trisomy 21 → caused by nondisjunction OR a robertsonian translocation between chromosomes 21 and 14

• low-set nasal bridge and ears, epicanthal folds around nose, upslanting palperbeal fissure eye openings, flattened fact, developmental and intellectual delays, hypotonia, light brushfield spots around iris

• increased risk for congenital heart disease leukemia and GI problems

• Most common aneuploid condition

Edward Syndrome

• Trisomy 18 → caused by nondisjunction or translocation

• Congenital heart disease prevents most affected infants from surviving past first year

• surviving mosaic individuals usually have severe intellectual and growth delays, microretrognathia (small chin/mouth area), prominant occipital (back) part of skull, unusual grip and rocker-bottom feet

Patau Syndrome 

• Trisomy 13 → caused by either nondisjunction or translocation

• Congenital heart disease prevents most affected infants from surviving past first year

• Surviving mosaic individuals usually have severe intellectual and growth delays, cleft lip/palate, poly or syn dactyly, microcephaly, and kidney malformations

• least common aneuploid condition

Klinefelter’s Syndrome

• karyotype 47 xxy

• Tall and long stature with possible infertility/testicular atrophy (shrinkage)

Turner Syndrome

YOU!!!

• Karyotype 45 X0 → only monosomy viable with life → most likely to get the one x chromosome from mom, which is the opposite of what is seen in other aneuploidies

• symptoms → ovarian failure/infertility, short stature, possible coarctation/dissection (narrowing/tearing) of the aorta, skin webbing

• Does not usually cause intellectual disability, but growth and cognitive delays are much more severe when the condition arises from a ring-shaped x chromosome

47 xyyy

• often associated with different behavioral disorders (impulsivity, aggressiveness), to the point where it was believed to be correlated with chances of ending up in prison

• Other symptoms → tall stature, hypogonadism, undescended testes (but usually normal fertility)

Trisomy x

• usually have a pretty normal appearance, with some chances for slight developmental delay, tall stature, increased risk for cardiac defects and certain mental cinditions (ADHD, autism, bipolar, anxiety)

Pallister Killian Syndrome

• Isochromosome disorder → only short arm of chromosome 12 is present, in duplicate

• sparse hair/lashes, patches of hypopigmentation, low/stiff muscle tone, mental delays, increased risk of seizures and/or deafness

Cri-Du-Chat

• “Cry of the Cat” → named for the distinctive meowing-sounding cry infants with the condition have

• Caused by a Terminal deletion → one break on the short arm of chromosome 5 → 46,XX,del(5)(p13.3)

• other symptoms → growth and developmental delays, microcephaly, round moon-shaped face with wide-spaced, down-slanting eyes

17q21,31

• Interstitial deletion → caused by two breaks on the long arm of chromosome 17 that are fused back together

• bulbous nose, ptosis (droopy eyes), some developmental delay, seizures

DiGeorge Syndrome

• microdeletion in a repeated region on chromosome 22 (22q11.2)

• symptoms → long face with hooded eyes, potential speech and language delays, cleft palate, risk for immune mental and cardiac cinditions (Tetralogy of Fallot, Schizophrenia, Bipolar), hypocalcemia

• its complimentary duplication carries essentially the same symptoms, except microcephaly, ADHD, aggressive behavior, and./or mild developmental delay are more common

Cat Eye Syndrome

• caused by inverted duplication of a region on chromosome 22

• Symptoms → cotoboma (gap in ) iris, congenital heart disease, wide-spaced eyes, mild developmental delay, ear tag

Roberts Syndrome

• Autosomal Recessive

• Cebtromeres impaced → sister chromatids don’t remain attached

• Limb and craniofacial deformaties, growth and developmental delays

9;22 translocation

• Aquired - happens in somatic cells

• Balanced - but only one of the products contributes to disease, based on the proximity of the involved genes

• produces a chimeric fusion gene/protein → the part of the ABL1 gene from chr 22 that has tyrosine kinase activity when brought in close contact to other proteins, with the part of the BCR gene from chr 9 that always dimerizes

• Product → an always active tyrosine kinase that could send unregulated cell proliferation signals → cancer

Ewing Sarcoma

• Aquired - happens in somatic cells

• Balanced 11;22 transloction - but only one of the products contributes to disease, based on the proximity of the involved genes

• Bone tumor caused by a chimeric fusion gene product of FLI1

Acute Promyelocytic Leukemia

• Aquired - happens in somatic cells

• Balanced 15;17 translocation - but only one of the products contributes to disease, based on the proximity of the involved genes

• Chimeric fusion product of RARA and PML genes represses a gene that would normally promote white blood cell differentiation, leading to a tumor forming from immature blood cells

• A treatment does exist, but must be delivered quickly to avoid bleeding complications - this is where genetic testing comes in

Burkitt Lymphoma

• Aquired - happens in somatic cells

• Balanced translocations with chromosome 8

• Enhancers being moved in front of the Myc gene for cell growth, proliferation, and apoptosis causes over expression, and can cause lymphatic tumors

HER-2/ERBB-2

• a genomic gain on chromosome 17 causes amplification of epidermal growth factor receptors, and can cause breast cancer

• Highly treatable - if this type of cancer is detected early enough via FISH analysis, Herceptin can reduce recurrence rates and mortality

Xenoderma Pigmentosa

• Autosomal Recessive

• Chromosomal Instability Syndrome - germline change that leads to increased risk for cellular damage

• Derma → symptoms include skin conditions and increased risk for skin cancer

• Caused by excision repair mechanisms being inhibited from properly removing UV damage from DNA

Fanconi Anemia

• Autosomal Recessive

• Anemia → bone marrow failure causes lack of blood cells

• two chromosomes with a broken chromatid are “repaired” together in a quadriradial - can cause blood (leukemia) and skin (squamous cell carcinoma) cancers

Ataxia Telangiectasta

• Autosomal Recessive change in the ATM gene on chr 11

• Ataxia - un stable/coordinated movements

• Telangiectasta - enlarged capillaries

• unstable detection and repair of breaks can lead to recurrent secondary translocations, namely w/ chromosomes 7 and 14

Bloom Syndrome

• Autosomal Recessive

• Features include dwarfism and butterfly rash

• prone to solid tumors (non-blood cancers) and higher rates of sister chromatid exchange

Cornelia De Lange Syndrome

• synophris (unibrow)

• short nasal bridge with upturned tip

• Downturned mouth

• long and smooth philtrum @ upper lipF

Fetal Alcohol Syndrome

• more of a rule-out scenario for genetics

• dysmorphic features → shorter palperbal fissure eye openings, smooth filtrum of upper lip, flattened/hypoplasic cheeks, low nasal bridge

Pompe Disease

• lysosomal and glycogen storage disorder → affects glycogen breakdown

• Muscle weakness, motor delay, respiratory and cardiac problems

• Diagnosed via newborn screening and/or GAA gene or enzyme efficiency testing

Beckwith Wiedemann Syndrome

• methylation defect

• Neonatal hypoglycemia, macroglossia, omphalocele, tumors