Sickle cell anemia
Single base mutation of codon #6 of beta-globin gene: Glu –> Val; novel property
Sickle cell trait
HbS/HbA (_2_2)
Hemoglobin C
Single base mutation of codon #6 of beta-globin gene: Glu –> Lys
Hemoglobin C trait
HbC/HbA (_2_2)
Hemoglobin E
Single point mutation in beta globin gene at position 26, changing Glutamic Acid –> Lys leading to splicing problems (structural change)
Hemoglobin SC
_S/_C
Thalassemia
Markedly reduced or no synthesis of one globin type
_-thalassemia-1
Deletion of both alpha globin genes on both homologs
_-thalassemia-1 trait
Deletion (50% decrese) of alpha globin gene on same homolog
_-thalassemia-2 trait
Deletion (50% decrese) of one alpha globin gene on both homologs (-/-) = African; (__/–) = SE Asia
-thal-1/-thal-2
25% of normal alpha globin levels
_-thalassemia major
No beta globin
_-thalassemia minor
Only one beta globin gene
Simple _-thalassemia
Mutations or deletions that impair production of beta globin chain alone
Complex _-thalassemia
Large deletion that remove beta globin gene plus other genes in the beta cluster or the LCR
Hemoglobin Kempsey
Asp99Asn missense mutation; gain of function mutation
HPFH
HbF (gamma globin) still active in adults instead of transition to beta globin
HbH
_-/–
Turner Syndrome
Absence of two complete copies of X (45X)
Klinefelter Syndrome
47XXY
Down Syndrome
Trisomy 21 normally due to nondisjunction from maternal gamete
Edwards Syndrome
Trisomy 18
Patau Syndrome
Trisomy 13
XX Male
Translocation of Y/autosomal chromosome due to unequal crossing over in paternal gamete meiosis
XY Female
Deletion of SRY (Yp11.3) or duplication of DAX1 (Xp21.2-p21.3)
Duchenne Muscular Dystrophy
Loss of function of DMD gene
Becker Muscular Dystrophy
Abnormal quality or quantity of dystrophin (DMD gene)
Hemophilia A
22A inversion on X chromosome causes this X-linked recessive disease characterized by deficiency of Factor VIII
Fragile-X Syndrome
Trinucleotide repeat disorder (CGG) due to mutation of 5’ UTR FRM1 gene (failure to express FMRP protein); > 200 CGG repeats leads to hypermethylation that inactivates the FMR1 promoter and thus a loss FMRP expression
Fabry Disease
X-linked deficient in alpha-galactosidase A activity which is a lipid, due to improper cleaveage. or can happen with a point mutation that doesn’t allow for proper folding of prot that cleaves the glucosphingolipid. Recombinant Alpha-Gal
Chronic Myelogenous Leukemia
Translocation of Abl gene from chromosome 9 to chromosome 22 with BCR gene which turns on tyrosine kinase activity, allowing certain blood cells to grow uncontrollably
Acute Myeloid Leukemia (M1/M2)(AML)
Translocation of ETO gene from chromosome 8 to chromosome 21 with AML1 gene
Acute Promyelogenous Leukemia (PML)(APL)
Subtype of AML caused by translocation of PML gene from chromosome 15 to chromosome 17 with RARA gene that blocks cell differentiation
Acute Lymphoblastic Leukemia (ALL)
B cell deficiency due to t(1:14)
I-cell disease
Lysosomal storage disease due to a failure to add a PO4 group to mannose lysosomes
Homocystinuria
Poor/absent binding of the cofactor to the custathionine synthase apoenzyme
_1-antitrypsin Deficiency (ATD)
Deficiency in SERPINA1 (aka ATT) which normally regulates elastase to prevent elastin destruction in connective tissues of the lung
Phenylketonuria
PAH (phenylalanine hydroxylase) defect which normally converts Phe –> Tyr and is a BH4 cofactor (for epinephrin and serotonin synthesis)
Tay-Sachs Disease
HEXA (hexosaminidase A) defective
Sandhoff Disease
HEXA (hexosaminidase A) and HEXB (hexosaminidase B) defective
AB-variant of Tay-Sachs
GM2 accumulates due to a defect in the GM2 activator protein (GM2-AP)
Wilson’s Disease
ATP7B gene mutation prevents adequate copper removal
Congenital Adrenal Hyperplasia
Cortisol levels too low, androgens become too high, overproduction of T
Friedreich’s Ataxia
GAA repeat in an intron of FXN gene which codes frataxin protein
Alpha-1 AT
deficiency in alpha-1 antitrypsin, elastases blocked
Pompe Disease
lack of alpha-glucosidase. Lysosomal storage issue. Musc fibers destroyed by glycogen deposition
Gaucher’s Disease
Lysosomal storage disease characterized by deficiency of glucocerebrosidase that causes an accumulation of glucocerebroside in lysosomes causing macrophage enlargement leading to fibrillar or striated apperance
Acute Intermittent Porphyria
Deficiency of porphobilinogen deaminase in heme production pathway causes a stall and buildup of porphobilinogen (intermediate) in cytoplasm
Achondroplasia
Mutation in FGFR3 gene (tyrosine kinase receptor) that substitutes G for A or G for C (Gly380Arg) on chromo 4. Only heterozygote muts are viable. Gain of function mutation. 1/40,000 births
Neurofibromatosis Type I
Loss of function mutation of NF1 (neurofibromin) which is a tumor suppressor gene on chromo 17
Marfan Syndrome
Mutation of FBN1 gene which is an extracellular matrix protein. The mutt makes a non-functional fibrillin protein from chromo 15.
Polycystic Kidney Disease (PKD)
Truncation of polycystin 1 and/or 2 proteins due to PKD1 (chromo 16) and PKD2 (chromo 4) mutations respectively
Familial Hypercholesterolemia
Mutation in LDL receptor gene
Huntington Disease
Trinucleotide repeat disorder of CAG on chromosome 4 with glutamine expansion in HTT gene (exon); paternal transmission bias
Myotonic Dystrophy
Maternal preference with CUG or CCTG repeat. Type 1 repeat in 3’ UTR, Type 2 in intron on DM gene
Osteogenesis Imperfecta Type I
Nonsense/frameshift mutation in COL1A1. Loss of function with abnormal pro_-1 collagen strand
Osteogenesis Imperfecta Type II, III, IV
Pro_-2 has added/missing piece, disallows proper collagen folding
Hereditary Neuropathy with Liability to Pressure Palsies
Deletion of part of PMP22 gene and then remaining piece is recombined with homolog
Charcot-Marie-Tooth
Duplication of PMP22 gene leads to gain of function on chromo 17
Familial Amyotophic Lateral Sclerosis (ALS)
Incomplete, age-dependent penetrance, allelic and genetic hetterogeneity through mutation in codon 4 of SOD1 gene + _ 4 other AD loci ALS (3,4,6,7)
Multiple Endocrine Neoplasia (MEN’s)
Multiple endocrine tumors due to mut in RET gene.
Deafness (Nonsyndromic)
can be AR due to allelic hetergeneity. GJB2 mutation causes 1/2 of all nonsyn. cases
Van der Woude
lower lip pits, cleft lip with or without cleft palate, and cleft palate alone , bad dentition
DiGeorge
Del on 22q chromo. The TBX gene is gone
Velocardiofacial Syndrome
Del on 22q chromo.
WAGR Syndrome
Contiguous gene deletion syndrome of PAX6 and WT1 on chromo 11p. Generally not inherited but caused by spontaneous deletion in eiosis or early fetal development.
OTC Disorder
Missing OTC gene that stops proper urea cycling function - can’t process many foods
Prader-Willi Syndrome
No active PWS gene due to paternal deletion and maternal silencing or double maternal gene
Angelman Syndrome
No active AS gene due to maternal deletion and paternal silencing
Progeria
Lamin A-C mutation, makes progerin that is targeted by nuc membrane Farnesyl groups
