week 4 - Sex-linked disorders/AD, AR Inheritance

Question 1

X-linked disorders are Caused by mutations in genes on the ———–

Answer 1

X chromosome

Question 2

A male with a mutated X-linked gene is known as ————– for that mutation

Answer 2

A male with a mutated X-linked gene is known as
hemizygous for that mutation

Question 3

X-dominant disorders affects?

Answer 3

Females
(Rarely males)

Question 4

X-linked recessive (XLR) disorders manifest in ———–

Answer 4

Hemizygous males
(they do not manifest in Heterozygous females)

Question 5

In what cases can Heterozygous females show features of X-linked recessive disorders?

Answer 5

X-inactivation (Skewing)

Question 6

Examples of XLR disorders

Answer 6

1) Duchenne muscular Dystrophy
2) Haemophilia A
3) G6PD
4) X-linked colour blindness
5) ATRX (alpha thalassaemia mental retardation
syndrome)

Question 7

CM of Duchenne muscular Dystrophy

Answer 7

1) Progressive muscle weakness
2) Wheelchair dependency
3) Cardiomyopathy
4) Delayed motor milestones

Question 8

MOI of Duchenne muscular Dystrophy

Answer 8

X-linked Recessive Disorders
(Males affected mostly)

* Female carriers may show symptoms based on
patterns of X inactivation

Question 9

XLR disorders are passed on to males by carrier mothers or fathers?

Answer 9

Carrier Mother
(No male-male transmission)

Question 10

MOI?

Answer 10

X-linked recessive

Explanation:
1- we can see that males are only affected
2- skips a generation so recessive moi

Question 11

X-linked dominant disorders where both males and females are affected?

Answer 11

X-linked hypophosphataemic rickets

Question 12

X-linked Dominant disorder affecting females only

Answer 12

Incontinentia pigmenti

Question 13

MOI?

Answer 13

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

Question 14

In cases of XLD disorders all affected fathers pass the diseases to their [daughters/sons/both]

Answer 14

only to their daughters

Question 15

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)

Answer 15

50%

Question 16

CF of Incontinentia Pigmenti

Answer 16

1) Dental abnormalities
2) Rentinal Hypervascularization
3) Blistering
4) Swirling macular hyperpigmentation
5) Abnormal pitted nails

Question 17

MOI of Incontinentia Pigmenti

Answer 17

XLD disorders
(affects females only)

Question 18

Clinical findings :
* increased renal phosphate loss
* spontaneous dental abscess
* Affects males and females equally
* bowing of the lower extremities

diagnosis?

Answer 18

X-linked Hypophosphataemia
(XLD disorder)

Question 19

Y-linked traits only affect?

Answer 19

males

Question 20

how does Y-linked inheritance work?

Answer 20

Males pass traits to all their sons
and to none of their daughters

Question 21

Examples of Pseudo-autosomal inheritance disorders

Answer 21

LWD - Leri-Weill Dyschondrosteosis
(SHOX gene)

Question 22

CF of Leri-Weill Dyschondrosteosis (LWD)

Answer 22

• Short stature
• Mesomelia
• Madelung deformity

Question 23

Leri-Weill dyschondrosteosis (LWD) are caused by mutations in ——– gene

Answer 23

SHOX gene
(SHOX happloinsuffuciency)

Question 24

———– : 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)

Answer 24

Pseudo-autosomal inheritance

Question 25

Autosomal recessive inheritance are caused by what type of Mutations?

Answer 25

Loss of function mutations

Question 26

Examples AR disorders

Answer 26

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

Question 27

beta thalassaemias is caused by?

Answer 27

Loss-of-function mutations in the **HBB** gene | * AR disorder

Question 28

CF of Beta thalassemia

Answer 28

1) **Sever microcytic anemia** 2) Herterozygous carries --> assymptomatic but--> **slightly anemic** w/ reduced MCH and MCV

Question 29

MOI of beta thalassemia?

Answer 29

**AR** disorder (loss of function in the HBB gene)

Question 30

MOI of Sickle cell disease

Answer 30

AR

Question 31

Sickle cell disease is an AR disorder caused by **p.Glu6Val** mutations in **------** gene

Answer 31

Sickle cell disease is caused by **p.Glu6Val** mutations in **HBB** gene | * like Beta thalassemia

Question 32

CF of Sickle cell disease

Answer 32

* Vaso-occlusive events * Chronic haemolytic anaemia

Question 33

Sickle cell disease is caused by Homozygous **-------------** mutation in the β-globulin gene that causes polmerization of **HbS (Hemoglobin S)** allele

Answer 33

**Missense mutation**

Question 34

MOI of Tay Sachs disease (HEXA disorder)

Answer 34

AR

Question 35

Tay Sach disease is caused by?

Answer 35

Loss of beta-hexosaminidase A (**HEX A**) enzyme activity

Question 36

Tay Sachs disease is **----------** disorder

Answer 36

Lysosomal storage , AR

Question 37

CF of Tay Sachs disease

Answer 37

* **Cherry-red spot** * loss of motor skills and progressive weakness (in 3-6 months yr olds) * Changes in vision * increased startle response

Question 38

**--------:** The phenomenon that a genetic disorder can be caused by mutations in a number of different genes

Answer 38

Locus Heterogeneity

Question 39

A disroder that demonstrates Locus Heterogeneity

Answer 39

AR deafness

Question 40

Consanguinity?

Answer 40

**Parents related to each other (cousins)** are more likely to bear children w/ very rare **AR disorders** (for the specific population)

Question 41

AD diseases are caused by what type of mutations?

Answer 41

1) Loss of function mutations 2) Gain of Function mutations 3) Dominant negative mutations 4) New RNA function

Question 42

Examples of AD disorders

Answer 42

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

Question 43

Tuberous sclerosis are caused by mutations in **---------** genes

Answer 43

**TSC1, TSC2**

Question 44

MOI of Tuberous sclerosis

Answer 44

AD

Question 45

CM of Tuberous sclerosis

Answer 45

1) Angiofibroma 2) Retinal hamartoma 3) Ungual fibromas 4) Hypomelanotic macules 5) Renal Angiomyolipomas 6) Shagreen patch 7) Fibrous cephalic plaques

Question 46

AD inheritance and gain-of-function mutations disorders

Answer 46

1) **Achondroplasia** - FGFR3 mutation 2) **Charcot-Marie Tooth** (CMT 1A) - PMP22 duplicatin

Question 47

Achondroplasia is an **---------** disorder caused by mutation in **-----------** gene

Answer 47

Achondroplasia is an **AD** disorder caused by mutation in **FGFR3** gene

Question 48

Charcot-Marie-Tooth (CMT 1A) is an **-------- disorder, ---------- mutation** disorder caused by **-----------** duplication

Answer 48

Charcot-Marie-Tooth (CMT 1A) is an **AD disorder, Gain of fxn mutation** disorder caused by **PMP22** duplication

Question 49

Familial Hypercholesterolaemia is an **------** disorder caused by **----------** mutation

Answer 49

Familial Hypercholesterolaemia is an **AD** disorder caused by **LDLR** mutation

Question 50

**---------------**: the phenomenon of two parents, who are unaffected by an AD disorder, having more than one child affected by the specific AD disorde

Answer 50

**Germline (gonadal) mosaicism**