Single Gene Disorders

Question 1

autosomal recessive inheritance is sometimes referred to as…

Answer 1

horizontal transmission

Question 2

Answer 2

2/3

Question 3

What is Fanconi Anemia and what is it a good example of?

Answer 3

Carriers of Autosomal Recessive conditions are not always unaffected

FA is caused by biallelic BRCA2 pathogenic variants

Phenotype of parents: Increased cancer risk

Phenotype of patient with FA: Bonemarrow failure, Pancytopenia, Short stature, Skeletal malformations, Renal abnormalities, Hearing loss, Microcephaly, AML, Solid tumors

Question 4

What is the inheritance pattern of most metabolic conditions?

Answer 4

autosomal recessive inheritance

Question 5

What is pseudodominant inheritance?

Answer 5

Pedigree looks dominant, actually is an autosomal recessive condition

Seen in condition with high carrier frequencies (CF, GJB2)

Question 6

What type of inheritance is this?

Answer 6

X linked inheritance
Clues:
No male to male transmission!
Females may be unaffected or more mild

Question 7

Why are X-linked male lethal conditions difficult to identify?

Answer 7

Can look like only females in a family are affected
Often will see recurrent pregnancy losses, stillborn males, etc

Question 8

Common Disorders with Autosomal Dominant Inheritance

Answer 8

BRCA1/BRCA2-associated hereditary breast and ovarian cancer
Familial Adenomatous Polyposis
Achondroplasia
Noonan Syndrome
Marfan Syndrome
Autosomal dominant polycystic kidney disease
Neurofibromatosis type 1 (NF1)
Hypertrophic cardiomyopathy (MYBPC3, MYH7)
Familial hyperlipidemia

Question 9

Common Disorders with Autosomal Recessive Inheritance

Answer 9

Metabolic conditions – PKU (phenylketonuria), MSUD (maple syrup urine disease), MCAD (medium-chain acyl-CoA dehydrogenase deficiency)
GJB2-related hearing loss
Ataxia telangiectasia
Fanconi Anemia
Cystic fibrosis

Question 10

Common disorders with X-linked Inheritance

Answer 10

X-linked Alport syndrome - Females more mildly affected
Rett syndrome (neurodevelopmental diagnosis seen in girls) - Male lethal
Duchene muscular dystrophy – Carrier females at risk for DCM
Adrenoleukodystrophy – Females at risk for later onset condition
Fabry disease (metabolic condition) – Females more mildly affected

Question 11

What is the difference between sex-linked vs sex-limited?

Answer 11

Sex-Linked – traits due to genes present on either X or Y chromosome

Sex-Limited – trait is expressed (or not expressed) due to anatomical or physiological differences

Question 12

How might a mother of a child with Duchenne Muscular Dystrophy present?

Answer 12

Female ‘carriers’ are not always unaffected.
Phenotype of son:
delayed motor milestones,
proximal weakness, gait
abnormalities,
dilated cardiomyopathy,
respiratory complications
Phenotype of mothers:
Increased risk for
dilated cardiomyopathy,
can have mild muscle
weakness, fatigue and
muscle pain or cramping

Question 13

X-linked female limited condition:
Pathogenic variants in
PCDH19 (located on the
X chromosome) cause
female limited epilepsy
and intellectual
disability
Males who carry
pathogenic variants in
PCDH19 are unaffected
What is the mechanism for this?

Answer 13

Mosaicism
this defies how we normally think about x-inked conditions.
All females are mosaic to some extent.
The presence of PCDH19 and not is the mechanism for this disease.
Males can’t be mosaic for X linked because they only have 1 X

Question 14

Examples of conditions often caused
by mosaic variants

Answer 14

• Vascular malformations
• Epidermal nevi
• Asymmetric growth disorders (PIK3CA)
• Congenital melanocytic nevi (RASopathies)
• Chromosomal disorders (Turner syndrome)
• However, nearly every autosomal dominant
  condition can be mosaic!

Question 15

How do we treat patients found to have a mosaic variant? (for example, variant shows in 15% of sequencing reads)

Answer 15

Like any other person with the syndrome because we don’t know how they are affected. We aren’t going to biopsy every possibly affected organ and even that wouldn’t work because we could miss the variant cells.

Question 16

Is the recurrence risk for the sibling of a person with a mosaic variant (ex: 15% of sequencing reads)?

Answer 16

<2% AKA same as gen pop because mosaicism is a post-zygotic change so it is not inherited.
The affected person’s children may or may not be at risk depending on whether there is gonadal mosaicism present. Testing on embryo/pregnancy is only way to check.

Question 17

What is the main reason why we never say a 0% recurrence risk for a family that has one child with what appears to be a de novo condition?

Answer 17

gonadal mosaicism
Gonadal mosaicism: an asymptomatic
individual carries a somatic variant isolated to
reproductive cells

Question 18

What is uniparental disomy?

Answer 18

both chromosomes are inherited from the same parent

Question 19

What is heterodisomy?

Answer 19

2 homologous chromosomes from the same parent (nonsegregation in stage I meiosis)

Question 20

What is isodisomy?

Answer 20

2 sister chromatids of one homologous chromosome from the
same parent (non-segregation in stage II meiosis)

Question 21

segmental uniparental disomy

Answer 21

UPD of only a segment of one chromosome, with
biparental inheritance of the remainder

Question 22

Can imprinting disorders be detected on sequencing tests?

Answer 22

No

Question 23

Beckwith-Wiedemann Syndrome (BWS)

Answer 23

Imprinting disorder
Chromosome 11p15.5
Congenital macroglossia (large tongue)
– Can obstruct breathing/interfere
with feeding
~50% of cases are caused by loss of methylation of IC2 on the maternal chromosome - uniparental disomy is 2nd leading cause tired with unknown
- this leads to overgrowth… Fathers wants a LARGE baby