A.k.a velocardiofacial syndrome

Microdeletion on long arm of chromosome 22

(test by FISH)

May involve  issue with neural crest cell migration

Most often a de novo mutation

Autosomal dominant

 Long arms, fingers, toes, pidgeon breast, scolisis, myopia

Can lead to aortic dissection

Autosomal dominant

Most often is a new mutation

Horizontal pattern of inheritance

Males and females equally affected

Both parents carry mutation --> 25% of being affected

Think consanguinity

Incidence much higher in males and females

All daughters of affected males will be carriers

No male-to-male transmission

Sons of carrier females have 50% chance of being affected and 50% of being unaffected

Daughters of carrier females - 50% chance of being a carrier

Inherited from mother only

Males and females are at risk of being affected

All daughters are at risk of transmitting the condition

Affected males cannot pass the condition to their children

Heteroplasmy

(think mitochondria)

Mitochondria in a cell is heterogeneous for mtDNA that causes human disease

- deletion mutations that arise de novo are always heteroplasmic

Homoplasmy

(think mitochondria)

All mitochondrial DNA in the organism is the same

Point mutations are generally homoplasmic and milder than deletions

X-linked

Males are generally more severely affected than females

Full mutation - >200 repeats

Trait appears either earlier or more severe in subsequent generations

Seen in Fragile X, Duchenne muscular dystrophy and Huntington disease

Centromere is in the center

(Submetacentric - not quite in the center,

acrocentric - on one end)

Different genes can cause the same disorder

Example - osteogenesis imperfecta

Trisomy 21 (Down syndrome)

Trisomy 13 (Patau syndrome)

Trisomy 18 (Edwards syndrome)

One of the chromatids "lags" in meiosis; it is not incorporated into the nucleus of one of the daughter cells and is subsequently lost;

As a result, a mosaic is created - normal cells plus cells with monosomy

45,X (a functional X chromosome is absent)

Symptoms - short stature; broad chest, low hairline, webbed nec; amenorrhea and infertility;

often congenital heart disease also present

Between acrocentric chromosomes (13, 14, 15, 21, 22)

2 long arms join at centromere resulting in one giant chromosome; short arms are lost

6 possible gametes - 1 normal, 1 balanced, 2 monosomies, 3 trisomies

If identical chromosomes are translocated (21:21) - all gametes are unbalanced

5p deletion syndrome

 Mental retardation, unusual facial features, behavioral problems

Tightly packaged

Less transcription

Random

XIST gene expressed by inactive X; product - large rRNA that coats inactive chromosome and changes it to heterochromatin

 Pseudoautosomal region - region that remain active; outside this region some genes also escape inactivation

Barr body - inactivated X in females

If some of the X chromosome translocated onto autosome and not inactivated - will have issues

Imprinted genes are reset in gametes to reflect new parent of origin

Both due to imprinting issues in 15q11-q13

PWS - paternally imprinted genes not expresses

AS - maternally imprinted genes not expressed

Both cases - mostly due to deletion in that region; some have uniparental disomy; some have imprinting issues

 Test - karyotype with FISH (deletion), methylation-specific PCR (imprinting defects); DNA polymorphism testing (UPD)

Look at chromosome number and gross chromosomal structure

Can be routine or high resolution

Check for presence of sequence of interest; especially if too large for PCR

Good for looking for methylation differences

Look for microscopic deletions or duplications

Use specific probes - so need to know what you're looking for.

Look for copy-number variants

Does not require prior knowledge of chromosomal location of any variant

Looks for submicroscopic deletions or duplications

Probes are in form of microarray

Competitive - add DNA of interest and DNA of a normal control, labeled with different fluorescent dyes and allow them to hybridize to probes in microarray

Looks at DNA sequence for specific mutations (point mutations, small deletions, insertions)

Does not detect large deletions

p + q = 1

p^2 + 2pq +q^2 = 1

When q^2 is rare,  p is close to 1 and thus heterozygotes are 2q

Test maternal serum

Elevated AFP levels in neural wall defects (i.e. spina bifida) and abdominal wall defects

Decreased in Trisomy 18 and Trisomy 21

Single nucleotide polymorphism

Polymorphic variation of a single nucleotide within a species

Neural tube and abdominal wall defects (AFP)

Trisomy 21 and 18

 Cystic fibrosis

Spinal muscular atrophy

Ashkenazi Jews carrier panel

13-23 weeks

AFP

Karyotype

Enzymatic studies (metabolic disorders)

DNA test

11-14 weeks

Karyotype

Enzymatic studies

DNA analysis

No AFP because no amniotic fluid

Can see placental mosaicism

Autosomal dominant

Often new mutation

Issues with collagen

Recognize by blue sclera (because it's very thin)

Many types

Hemophilia A and B

von Willebrand - very common; deficiency of factor required for platelet adhesion

Platelet disorders

Deficiencies in any clotting factors

Dominant inheritance

Spontaneous bleeding

Arterial-venous malformations