2 Patterns of Autosomal Inheritance

Question 1

What is mendelian inheritance?

Answer 1

Mendelian inheritance is patterns of single gene inheritance, pedigree analysis. It can be autosomal (1-22) or sex-linked (X or Y). It can be domiant or recessive.

Question 2

What is germline mosaicism?

Answer 2

The presence of more thatn one genetically distinct cell line

Question 3

What is autosomal DOMINANT inheritance?

Answer 3

Autosomal Dominant (AD) inheritance is when only one copy of a mutated gene is need for expression, then the pathogenic variant is said to be dominant.

Question 4

What is autosomal RECESSIVE inheritance?

Answer 4

Autosomal Recessive (AR) inheritance is when two pathogenic variants of a gene are needed to show clinical expression.

Question 5

What are the idealized features of a pedigree for autosomal dominant inheritance?

Answer 5

No skipped generations, equal numbers of males and females affected. Approximately 50% of children of an affected individual will themsleves be affected.

Question 6

What is retinoblastoma?

Answer 6

An eye cancer that begins in the back of the eye (retina), most commonly in children.

Question 7

What pattern of inheritance does retinoblastoma follow?

Answer 7

Autosomally dominant

Question 8

What are examples of autosomal dominant disorders?

Answer 8

Familial hypercholesterolemia, neurofibromatosis type 1, marfan syndrome, achondroplasia

Question 9

What phenotypes is neurofibromatosis type 1 characterized by?

Answer 9

Café-au-lait macules (spots), axillary/inguinal freckling, neurofibromas, lisch nodules (iris hamartomas), bony lesions (tibial bowing)

Question 10

What is the pattern of inheritance for neurofibromatosis type 1?

Answer 10

AD - Penetrance virtually 100% (diagnosed by 6), expressivity highly variable even within a family, de novo or new mutations account for half of all cases, genetic test is rare because clinical criteria is sufficently sensitive and specific

Question 11

What phenotypes are characteristic of Marfan syndrome?

Answer 11

FBN1 gene, fibrillin protein, dilated aortic root, ectopia lentis, skeletal changes, dural ectasia

Question 12

What pattern of inheritance does Marfan syndrome follow?

Answer 12

Autsomal Dominant, 25% de novo mutations, rare germline mosaicism

Question 13

What is achondroplasia?

Answer 13

The most common form of short-limbed dwarfism

Question 14

What is the pattern of inheritance for achondroplasia?

Answer 14

Autosomal dominant, 50% chance of parent of having an affect child, complete penetrance, 80% are de novo (100% in father’s germline and seem related to increase age >35 years, homozygotes for the mutation hav a poor prognosis (generally considered lethal)

Question 15

In achondroplaisa, the FGFR3 pathogenic variants cause what phenotypes?

Answer 15

Abnormal bone growth (results in short stature), rhizomelic shortening of the arms and legs, macrocephaly, frontal bossing, depressed nasal bridge

Question 16

G1138A is 98% a pathogenic variant in what genetic disease?

Answer 16

achondroplasia

Question 17

How is achondroplasia characterized?

Answer 17

Short-limbed dwarfism, macrocephaly, skeletal and CNS complications, normal IQ, clincialy and genetically homogeneous

Question 18

What is the natural history of achondroplasia?

Answer 18

Infancy: Hypotonia (low muscle tone), DD in motor milestons (large head), intelligence and life span are usally normal, compression of the spinal cord and or upper airway obstruction increases risk in infacy, 7-8% of infants die from obstructive or central apnea which can be due to brainstem compression

Question 19

What is the genetic basis of achondroplasia?

Answer 19

Caused by mutations in the fibroblast growth receptor (FGFR) 3 gene, FGFR3 gene is a negative regulator of bone growth, mutations cuase activation of gene, hence inhibition of bone growth, “gain of function” mutation

Question 20

What is consanguinity?

Answer 20

The property of being from the same kinship as another person. This is seen more commonly in pedigrees involving rare recessive diseases, studies show increased mortality and morbidity among the offspring of first-cousin marriages. First cousin marriage (1/8 of DNA)

Question 21

What is the recurrence risk with somone who has a autosomally recessive disease?

Answer 21

For an affected individual, 100% risk of transmitting the gene to each child (risk to child based on partern’s risk). 50% chance each child with be carrier with unaffected couple and 2/3 will be unaffected carriers

Question 22

What are characteristics of autosomal recessive diseases?

Answer 22

Relatively uniform in expression of features, complete penetrance, early onset of symptoms, heterozygotes have 50% of normal function which is usally enough

Question 23

What are the pedigree feature of autosomal recissive diseases?

Answer 23

Affected individual born to unaffected parents, skipped generations, males and females equally affected, possible consanguinity

Question 24

What are autosomal recessive disorders?

Answer 24

Sickle cell anemia, Cystic fibrosis, Inborn errors in metabolism (PKU, galactosemia, homocystinuria, lysosomal storage disorders)

Question 25

What is sickle cell disease?

Answer 25

Sickle cell disease is a point mutation producing HbS (protective against malaria). Cells sickle under conditions of low pH or deoxygination. Heterozygotes have 40% HbS, homozygotes have 100%.

Question 26

What causes cystic fibrosis?

Answer 26

Cystic fibrosis is caused due to a mutation in CTFR, a chloride chanel.

Question 27

How is cystic fibrosis test for?

Answer 27

The gold standard laboratory test - sweat chloride test

Question 28

What population is cystic fibrosis most common in?

Answer 28

Caucasian, cystic fibrosis (CF) is the most common AR disorder 1/3200 births

Question 29

What are the clinical signs and symptoms of cystic fibrosis?

Answer 29

Neonatal - meconium ileus (bowel obstruction), abdominal calcifications. Infancy - failure to thrive, chronic diarhea, pneumonia. Childhood - nasal polyposis, intussusception(A condition in which part of the intestine telescopes into itself)

Question 30

What is the pathogenesis of CF?

Answer 30

Defective chloride secretion and sodium hyperabsorption lead to the depletion of the layer of surface fluid, with consequent breakdown of mucociliary transport

Question 31

What is phenylketonuria (PKU)?

Answer 31

PKU is the inability to process phenylalanine (PHE) into tyrosine due to phenylalanine hydroxylase deficiency

Question 32

What are the symptoms of PKU?

Answer 32

PHE accumulation causes brain damage, microcephaly, severe MR, and epilepsy. Some patients families report musty odor, eczema, and hypopigmentation

Question 33

What is the treatment for PKU?

Answer 33

Better outcome with good dietary management (low protein diet)

Question 34

What does variable expressivity mean?

Answer 34

Traits expressed vary between individuals who carry the gene, along a continuum. Intrfamily clinical variability (NF1 example - individual A has optic glioma, individual B has skin findings)

Question 35

What does reduced penetrance mean?

Answer 35

Defined as the percentage of people who carry the pathogenic variant who express the trait (Marfan syndrom - highly penetrant, no non-penetrance is reported)

Question 36

What is genetic heterogeneity mean?

Answer 36

The production of the same or similar phenotypes (observed biochemical, physiological, and morphological characteristics of a person determined by his/her genotype) by different genetic mechanisms. There are two types: (1) allelic heterogeneity – when different alleles at a locus can produce variable expression of a condition; and (2) locus heterogeneity – the term used to describe disease in which mutations at different loci can produce the same disease phenotype.

Question 37

What is a de novo mutation?

Answer 37

A genetic alteration that is present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis. Also called de novo variant, new mutation, and new variant.