ANEUPLOIDY

Abnormal chromosome number


Aneuploidy is an unusual number of chromosomes. Humans normally have 46 of them. Aneuploidies usually occur due to an error in meiosis.


Here’s what Meiosis usually looks like. 

In Sperm, this happens immediately after they’re created. 

In Eggs, this process is stalled at Meiosis 1 (Prophase) in utero, then is stalled a second time at Meiosis 2 (Metaphase) after ovulation. 


Here are the two ways meiosis can lead to aneuploidy.

This inability to separate is called meiotic nondisjunction. 

Trisomy - one extra chromosome (47)

Monosomy - one less chromosome (45)


Note - Aneuploidy can also happen due to an error in mitosis, but that’s less common. A mitosis error (somatic error) that occurs a few days after fertilization between the sperm and egg may result in a mosaic (patchy) pattern. 

MONOSOMY

Missing chromosome


Turner syndrome refers to the loss of one of the X chromosomes (XO). It’s the only survivable monosomy in humans. The remaining X can compensate, I suppose. There are two causes.


Meiosis (most common)- an error in meiosis (meiotic nondisjunction) of mom’s egg or dad’s sperm could result in all the child’s cells being deficient in an X chromosome. They would be 45 XO (the O refers to the absent X chromosome). 


Mitosis - an error in mitosis (somatic error) of the early embryo could result in a percentage of the child’s cells being deficient in an X chromosome. Some of the child’s body is affected (45 XO), but the rest is perfectly healthy (46 XX). 


There are a lot of pretty random symptoms caused by Turner’s Syndrome… This is very high yield.

Webbed neck

Karyotype with only one X chromosome

TRISOMIES

One extra chromosome


Trisomy means having an extra chromosome (47 chromosomes). There are 4 survivable examples. They are mostly (90%) caused by meiotic nondisjunction. One of them (Klinefelter) involves sex chromosomes. The other 3 involve regular chromosomes, and these 3 are all associated with old moms, intellectual disability, heart defects and physical deformities. Mom supplies the extra chromosome in 90% of cases (increased risk with advanced maternal age), since mom’s eggs are halted in Meiosis 1 prior to ovulation, which allows for the accumulation of more genetic mutations. In other words, a longer meiosis 1 = more mistakes. 

KLINEFELTER SYNDROME - extra copy of the X Chromosome in males (47 XXY). They mostly look like males (thanks to the Y chromosome), but they display many female characteristics (thanks to the extra X chromosome). They are sometimes described as eunuch-like. That includes their personalities, which are frequently described as being calm and unassuming. See the flowchart on the next page for more details.

DOWN SYNDROME - extra copy of chromosome 21 (Down syndrome is also called Trisomy 21). 95% of cases are caused by Meiotic Nondisjunction, 1% by Mitotic Error (mosaicism), and 4% are caused by a Robertsonian Transformation. A Robertsonian Translocation means that chromosome 21 fuses with another chromosome (usually 14), and this prevents normal chromosomal separation -- this one is passed down through families and isn’t associated with maternal age. Here are some of the unique characteristics seen in Downs: Epicanthal Folds (covered up inner corner of the eye), upslanting palpebral fissures (eyes slant Down in Down syndrome, forming a V shape), brushfield spots (white spots on iris), flat face, low ears, short neck, brachycephaly (posterior skull is flat), single transverse palmar crease, sandal gap (big space between 1st and 2nd toes), hypotonia and short stature. They are also at risk for some congenital organ malformations: endocardial cushion defects (ASD, VSD, Mitral Regurge) and GI disorders (Duodenal atresia, Hirschsprung). They also get Alzheimer’s disease at much higher rates, because the causative protein (Amyloid Precursor Protein) is found on 21c. Finally, they have a higher risk for leukemia (especially ALL or AML), particularly the M7 megakaryoblastic variety of AML. 


EDWARD SYNDROME - extra copy of chromosome 18 (Trisomy 18). Think of Edward’s as a more severe form of Downs (average survival is less than 1 year), with a different set of symptoms: prominent misshapen posterior skull, clenched fists with overlapping fingers, rocker bottom feet, small jaw, omphalocele and myelomeningocele. 


PATAU SYNDROME - extra copy of chromosome 13 (Trisomy 13). Patau Syndrome is the most severe Trisomy. In fact, it’s barely survivable. 95% of patients are dead before their first birthday. The physical deformities are usually so severe that they’re immediately identified on prenatal ultrasounds. They have a lot of problems with midline structures. Complications include cleft lip, cleft palate, post-axial polydactyly (extra pinky finger), holoprosencephaly (brain with a single lobe), cutis aplasia (red lesion at the top of the head), PCKD and endocardial cushion defects. 

Downs - Drinking age is 21

Edwards - Election age is 18

Patau - Puberty age is 13

Prenatal Screening Tests (QUAD Screen)

KLINEFELTER

XXY





Estrogen is what makes people tall, it drives long bone growth.




OTHER GENETIC CONDITIONS

Fragile X Syndrome is an X-linked dominant trinucleotide repeat of the FMR1 gene that causes intellectual disability, an elfin face and large testes. Fragile X is the most common familial cause of intellectual disability. The repeating DNA segment is CGG. Symptoms are typically present in XY individuals, but are mild or absent in XX individuals (the other X can compensate). 

pointy Chin, Giant Gonads

Rett Syndrome is a sporadic genetic mutation of the MECP2 gene on the X chromosome that leads to a sudden developmental regression in previously healthy young girls aged one to four. They develop problems with speech, intellect and movements. Their head shrinks. They begin having seizures and characteristic hand wringing. Although it seems like boys aren’t affected, in reality Rett syndrome is universally fatal in utero for XY individuals. 

RETTgression

CRI-DU-CHAT is a genetic deletion on chromosome 5 that leads to severe intellectual disability, high pitched “cat-like” crying, microcephaly, epicanthal folds and heart problems.

WILLIAMS SYNDROME is a genetic deletion on chromosome 7 that leads to intellectual disability despite excellent verbal skills, supravalvular aortic stenosis and an elfin face. They are extremely friendly with strangers. They are sometimes called “happy idiots,” and although I dislike that term, it’s a helpful memory tool. 

WILL you be my friend?

IMPRINTING DISORDERS




PRADER-WILLI SYNDROME is an imprinting disorder where the Parental copy of the PWS gene breaks, resulting in characteristic symptoms of hyperphagia (big appetite), obesity, hypotonia and intellectual disability.  Note that 25% of cases are due to uniparental disomy instead of a mutation on dad’s PWS gene. In other words, both of mom’s inactivated genes are inherited.


ANGELMAN SYNDROME is an imprinting disorder where the maternal copy of the UBE3A gene breaks, resulting in characteristic symptoms of severe intellectual disability, inappropriate laughter and ataxia. Only 5% of cases are due to uniparental disomy.