molecular - single gene disorders (substitutions and InDels)

cystic fibrosis

causes thick, sticky secretions throughout the body, classically a lung disease and affects the whole body

CFTR

cystic fibrosis has variants in _____ gene; chloride ion channel in epithelium, autoosomal recessive

F508del

what is the most common variant in the CFTR gene for cystic fibrosis?

ivacaftor

CF therapy: gate opening drug that primarily detectsG551D

lumacaftor/ivactor

CF therapy: chaperone drug that treats F508del homozygotes

tezacaftor/ivaftor

CF therapy: improved chaperone drug, treats F508del heterozygotes, increased life expectancy and quality of life

tezacaftor/elexacaftor/ivacaftor

CF therapy: further improvement of chaperone function, primarily treats F508del homozygotes and compound heterozygotes, predicted near normal life expectancy if treatment starts at age 6

tezacaftor/vanzacaftor/deutivacaftor

CF therapy: further refinement of chaperone function, lower side effect profile, wider eligibility

sickle cell anemia

causes sickling of RBCs, leading to vascular congestion, hemolysis, clotting and pain

HBB

sickle cell anemia causes SNP in _____, causes hemoglobin misfolding in anoxic states

sickle cell anemia

treatment: hydroxyurea, exchange transfusion, HSCT, gene therapies

lyfgenia

SCA therapy: inserts modified HbA gene via lentivirus

Casgevy

SCA therapy: induces production of HgF by disrupting enhancer for BCL11a via CRISPER/Cas9

hereditary hemochromatosis

disease of iron metabolism, causing excess iron build up throughout the body

HFE

hereditary hemochromatosis causes an SNP in _____

C282Y

the most common variant for hereditary hemochromatosis

H63D

this is only causative of hereditary hemochromatosis in compound with C282y

inherited coagulopathies

increased susceptibility to blood clots

factor V leiden

inherited coagulopathy of R506Q

hyperhomocysteinemia

inherited coagulopathy of MTHFR

hemophilia A

factor VIII, x linked recessive

hemophilia B

factor IX, x linked recessive, missense mutation in protease domain

hemophilia C

factor XI, autosomal recessive

vonwillebrand’s disease

vWF, type 1 and 2 are autosomal dominant, type 3 is autosomal recessive

osteogenesis imperfecta

brittle bone disease that is a connective tissue disorder, bones break easily, short stature, muscle weakness, hearing loss

osteogenesis imperfecta

19 subtypes, mostly collagen or collagen related genes

marfan syndrome

connective tissue disease with long limbs, tall stature, fragile blood vessels, hypermobile joints, cardiac rhythm abnormalities, ectopia lentis

FBN1

marfan syndrome causes a variant in _____

ehlers-denlos syndrome

connective tissue disease that causes joint hypermobility, soft skin, chronic pain, vascular rupture, unusual scars, skeletal abnormalities

ehlers-danlos syndrome

14 subtypes, mixture of autosomal dominant and recessive

alport syndrome

connective tissue disease that causes renal fibrosis, hearing loss, lenticonus, and aortic dissection

alport syndrome

affects type IV collagen genes

COL4a5

alport syndrome variant is x linked recessive and most of the cases

COL4a3 and 4a4

alport syndrome variant is autosomal recessive, variant in C terminus region, slower progressing

loeys-dietz syndrome

connective tissue disease that causes arterial aneurysms, pectus excavatum/carinatum, hypertelorism and cleft palate, and high risk of uterine rupture

TGF-beta

loeys-dietz variant that causes singling molecules regulating extracellular matrix

long QT syndrome

inherited cardiac condition that is disease of ion channels of heart, KNCQ1, KNCH2, SCN5A

brugada syndrome

inherited cardiac condition that is disease of ion channels of heart, SCN5A, KCNE5

familial hypertrophic cardiomyopathy

inherited cardiac syndrome that causes thickened walls of the heart, variants in sarcomeric protein

familial dilated cardiomyopathy

inherited cardiac syndrome that causes enlarged heart chambers and thinner walls

arrhythmogenic cardiomyopathy

inherited cardiac syndrome that causes fibrous/fatty infiltration of cardiac wall, 11 genes identified

x linked severe combined immunodeficiency

disease causing absence of T cells and NK cells, recurrent infection, IL2RG

x linked agammaglobulinemia

disease causing lack of B cells, BTK

chronic granulomatous disease

inability to form superoxides in immune cells, NOX2

RASopathies

changes to RAS/MAPK pathway, kinase signal transduction

neurofibromatosis type 1

RASopathy that causes neurofibromas and cafe-au-laite spots, NF1

noonan syndrome

RASopathy that has characteristic face shape, neck webbing, heart defects, and short stature; PTPN11, KRAS, SOS1, RAF1

charcot marie tooth syndrome

peripheral muscle weakness and sensation loss, additional manifestations based on subtype

hereditary sensory radiculopathy

young adult onset of sensory loss, with or without automatic or motor neuropathy

congenital insensitivity to pain

loss of pain and temperature sensation at birth, other sensation remains in tact, NGFB

congenital insensitivity to pain with anhidrosis

loss of pain and temperature sensation at birth, inability to sweat, NTKR1