week 4 - Sex-linked disorders/AD, AR Inheritance Flashcards
X-linked disorders are Caused by mutations in genes on the ———–
X chromosome
A male with a mutated X-linked gene is known as ————– for that mutation
A male with a mutated X-linked gene is known as
hemizygous for that mutation
X-dominant disorders affects?
Females
(Rarely males)
X-linked recessive (XLR) disorders manifest in ———–
Hemizygous males
(they do not manifest in Heterozygous females)
In what cases can Heterozygous females show features of X-linked recessive disorders?
X-inactivation (Skewing)
Examples of XLR disorders
1) Duchenne muscular Dystrophy
2) Haemophilia A
3) G6PD
4) X-linked colour blindness
5) ATRX (alpha thalassaemia mental retardation
syndrome)
CM of Duchenne muscular Dystrophy
1) Progressive muscle weakness
2) Wheelchair dependency
3) Cardiomyopathy
4) Delayed motor milestones
MOI of Duchenne muscular Dystrophy
X-linked Recessive Disorders
(Males affected mostly)
* Female carriers may show symptoms based on
patterns of X inactivation
XLR disorders are passed on to males by carrier mothers or fathers?
Carrier Mother
(No male-male transmission)
MOI?
X-linked recessive
Explanation:
1- we can see that males are only affected
2- skips a generation so recessive moi
X-linked dominant disorders where both males and females are affected?
X-linked hypophosphataemic rickets
X-linked Dominant disorder affecting females only
Incontinentia pigmenti
MOI?
X-linked Dominant
Explanation:
- all heterozygous females are affected and affected males are viable
- More females affected than males
- affected males pass the condition to all their daughters but non to their sons
In cases of XLD disorders all affected fathers pass the diseases to their [daughters/sons/both]
only to their daughters
In cases of XLD disroders affected women have a –% risk of passing on the mutation (and the condition) to each of their children (male or female)
50%
CF of Incontinentia Pigmenti
1) Dental abnormalities
2) Rentinal Hypervascularization
3) Blistering
4) Swirling macular hyperpigmentation
5) Abnormal pitted nails
MOI of Incontinentia Pigmenti
XLD disorders
(affects females only)
Clinical findings :
* increased renal phosphate loss
* spontaneous dental abscess
* Affects males and females equally
* bowing of the lower extremities
diagnosis?
X-linked Hypophosphataemia
(XLD disorder)
Y-linked traits only affect?
males
how does Y-linked inheritance work?
Males pass traits to all their sons
and to none of their daughters
Examples of Pseudo-autosomal inheritance disorders
LWD - Leri-Weill Dyschondrosteosis
(SHOX gene)
CF of Leri-Weill Dyschondrosteosis (LWD)
- Short stature
- Mesomelia
- Madelung deformity
Leri-Weill dyschondrosteosis (LWD) are caused by mutations in ——– gene
SHOX gene
(SHOX happloinsuffuciency)
———– : recomination of the 2 homologus regions at the tips of the short and long arms of the X and Y chromsome during meiosis –> Autosomal inhertiance pattern (rather than sex-linked)
Pseudo-autosomal inheritance
Autosomal recessive inheritance are caused by what type of Mutations?
Loss of function mutations
Examples AR disorders
1) Beta thalassaemias (HBB)
2) Sickle cell disease (HBB, Glu6Val)
3) Cystic fibrosis (CFTR)
4) Tay-Sachs disease
5) Wilson disease
6) HFE-associated Hereditary Haemochromatosis
7) AR retinitis Pigmentosa
8) Friedeich’s Ataxia
beta thalassaemias is caused by?
Loss-of-function mutations in the HBB gene
* AR disorder
CF of Beta thalassemia
1) Sever microcytic anemia
2) Herterozygous carries –> assymptomatic but–> slightly anemic w/ reduced MCH and MCV
MOI of beta thalassemia?
AR disorder
(loss of function in the HBB gene)
MOI of Sickle cell disease
AR
Sickle cell disease is an AR disorder caused by p.Glu6Val mutations in —— gene
Sickle cell disease is caused by p.Glu6Val mutations in HBB gene
* like Beta thalassemia
CF of Sickle cell disease
- Vaso-occlusive events
- Chronic haemolytic anaemia
Sickle cell disease is caused by Homozygous ————- mutation in the β-globulin gene that causes polmerization of HbS (Hemoglobin S) allele
Missense mutation
MOI of Tay Sachs disease (HEXA disorder)
AR
Tay Sach disease is caused by?
Loss of beta-hexosaminidase
A (HEX A) enzyme activity
Tay Sachs disease is ———- disorder
Lysosomal storage , AR
CF of Tay Sachs disease
- Cherry-red spot
- loss of motor skills and progressive weakness (in 3-6 months yr olds)
- Changes in vision
- increased startle response
——–: The phenomenon that a genetic disorder can be caused by mutations in a number of different genes
Locus Heterogeneity
A disroder that demonstrates Locus Heterogeneity
AR deafness
Consanguinity?
Parents related to each other (cousins) are more likely to bear children w/ very rare AR disorders (for the specific population)
AD diseases are caused by what type of mutations?
1) Loss of function mutations
2) Gain of Function mutations
3) Dominant negative mutations
4) New RNA function
Examples of AD disorders
1) BRCA1/2-Associated Hereditary Breast and Ovarian Cancer
2) Hirschsprung disease
3) Neurofibromatosis type 1 (NF1)
4) Charcot-Marie-Tooth Neuropathy Type 1A
5) Achondroplasia
6) COL1A1/2-Related Osteogenesis Imperfecta (OI)
7) Tuberous sclerosis (TBs)
8) Huntington disease (HD)
9) Myotonic Dystrophy Type I
10) Ehlers-Danlos syndrome (classic, hypermobility, vascular)
11) Marfan syndrome
12) Multiple Endocrine Neoplasia Type II
Tuberous sclerosis are caused by mutations in ——— genes
TSC1, TSC2
MOI of Tuberous sclerosis
AD
CM of Tuberous sclerosis
1) Angiofibroma
2) Retinal hamartoma
3) Ungual fibromas
4) Hypomelanotic macules
5) Renal Angiomyolipomas
6) Shagreen patch
7) Fibrous cephalic plaques
AD inheritance and gain-of-function mutations disorders
1) Achondroplasia - FGFR3 mutation
2) Charcot-Marie Tooth (CMT 1A) - PMP22 duplicatin
Achondroplasia is an ——— disorder caused by mutation in ———– gene
Achondroplasia is an AD disorder caused by mutation in FGFR3 gene
Charcot-Marie-Tooth (CMT 1A) is an ——– disorder, ———- mutation disorder caused by ———– duplication
Charcot-Marie-Tooth (CMT 1A) is an AD disorder, Gain of fxn mutation disorder caused by PMP22 duplication
Familial Hypercholesterolaemia is an —— disorder caused by ———- mutation
Familial Hypercholesterolaemia is an AD disorder caused by LDLR mutation
—————: the phenomenon of two parents, who are unaffected by an AD disorder, having more than one child affected by the specific AD disorde
Germline (gonadal) mosaicism
