Genetics and Genomics in Obstetrics

Genetics

• The study of genes, heredity, and the variation of inherited characteristics.
• Medical genetics focuses on the etiology and pathogenesis of human diseases with genetic origins.
• Medical genetics includes prediction and prevention of diseases.
• Genetic disease is common, affecting 2-3% of newborns with structural defects, increasing to 8-10% by age 18 with other abnormalities.

Genomics in Obstetrics

• The Human Genome Project completed in 2003, identified over 25,000 human genes to better understanding of disease biology.
• 99% of human DNA is identical, with variations every 200-500 base pairs as single-nucleotide polymorphisms.
• The human genome has over 80 million genetic variants.
• OMIM Includes >15,00 genes and nearly 500 mendelian and mitochondrial conditions with molecular basis (early 2017).
• The National Library of Medicine has a database called Genetics Home Reference (GHR), containing data on over 2400 genetic conditions and genes for patients and trainees.

Chromosomal Abnormalities

• Chromosomal abnormalities are significant in genetic disease.
• Aneuploidy accounts for over 50% of first-trimester & ~20% of second-trimester miscarriages, and 6-8% of stillbirths and early-childhood deaths.
• Trisomy 21 accounts for over half of aneuploidy cases.
• Trisomy 18 accounts for nearly 15% of cases.
• Trisomy 13 accounts for 5% of cases.
• EUROCAT tracks chromosomal abnormalities in Europe since 2000.

Standard Nomenclature

• Karyotypes use the International System for Human Cytogenomic Nomenclature.
• Abnormalities are categorized by chromosome number, like trisomy, & chromosome structure.
• Each chromosome has a short (p) arm and a long (q) arm, separated by the centromere.
• Karyotype reports list total chromosome number, sex chromosomes (XX or XY), & structural variations with standard abbreviations like del (deletion) and inv (inversion).
• Designations indicate precise abnormality location.
• Copy number variants use array designations to represent microdeletions or microduplications, starting with "arr" and the genome build version, like GRCh38.
• Information includes chromosome number, arm (p or q), specific bands, and base pair coordinates for accurate abnormality details.

Abnormalities of Chromosome Number

• The most recognizable chromosomal abnormalities are numerical.
• Aneuploidy means an extra chromosome (trisomy) or missing chromosome (monosomy).
• This differs from polyploidy, which is an abnormal number of haploid chromosome sets, like triploidy.

Autosomal Trisomies

• Autosomal trisomies account for approximately half of all chromosomal abnormalities.
• Trisomy usually results from nondisjunction, meaning that there is a failure in chromosomal pairing & separation during meiosis, which can happen if chromosomes don't pair, separate prematurely, or fail to separate.
• The risk of autosomal trisomy increases with maternal age, especially age 35+.
• Oocytes pause in meiosis I from birth until ovulation, sometimes for 50 years. Nondisjunction leads to trisomy if fertilized.
• The other gamete, with no copy will lead to monosomy if fertilized, and 10-20% of oocytes are aneuploid versus 3-4% of sperm.
• Trisomies other than 21, 18, or 13 are rare to have term pregnancy.
• Trisomy 13 and 18 often die before term.

Trisomy 21 - Down Syndrome

• The most common nonlethal trisomy.
• Associated with older maternal age.
• Affected females are fertile and⅓ of offspring inherit the disease.
• Affected males are almost always sterile.

Causes

• Trisomy 21 (95%)
• Robertsonian Translocation
• Isochromosome or Mosaicism

Trisomy 18 - Edwards Syndrome

• High in-utero lethality and affected pregnancies are often terminated.
• It is caused by chromosomal rearrangement.

Major Anomalies

• Heart defects, e.g. ventral septal defects.
• Cerebellar vermian agenesis.
• Myelomeningocele.
• Diaphragmatic hernia.
• Omphalocele.
• Imperforate anus. -Renal anomalies, e.g. horseshoe kidney.
• Cranial and extremity abnormalities, e.g. prominent occiput, micrognathia, clenched hands with overlapping digits.
• Radial aplasia with hyperflexion of wrists.
• Rockerbottom or clubbed feet.
• Strawberry-shaped cranium.
• Wide cavum septum pellucidum.
• Choroid plexus cysts.
• Pregnancies in the 3rd trimester often develop fetal growth restriction.
• Mean birthweight is <2500g.

Trisomy 13 - Patau Syndrome

• Highly lethal, and most affected fetuses are lost.

Causes

• Trisomy 13
• Robertsonian Translocation, der(13;14)(q10;q10)

Characteristic finding includes

• Holoprosencephaly.
• Microcephaly.
• Hypotelorism and nasal abnormalities.
• Cardiac defect.
• NTDs, such as cephalocele.
• Microphthalmia.
• Cleft lip and palate.
• Omphalocele.
• Cystic renal dysplasia.
• Polydactyly and rockerbottom feet.
• Skin aplasia.
• Ddx, cephalocele, cystic kidney and polydactyly is Meckel-Gruber Syndrome.

Prognosis

• One week survival rate is 40%.
• One year survival rate is 3%.
• Risk of hyperplacentosis and preeclampsia in pregnancy with trisomy 13 beyond second trimester.
• Chromosome 13 encodes soluble fms-like tyrosine kinase-1 (sFlt-1), an antiangiogenic protein is overexpressed in trisomic 13 associated with preeclampsia.
• Trisomy 9, 22, 16 is most common for 1st trimester loss.

Monosomy

• Nondisjunction creates an equal amount of nullisomic and disomic gametes.
• Almost all monosomic conceptuses are lost before implantation.
• The exception is Turner syndrome, a monosomy for the X chromosome (45, X).
• Maternal age and monosomy are not linked.

Polyploidy

• It's an abnormal number of complete haploid chromosomal sets.
• It accounts for 20% of spontaneous abortion.
• Triploid pregnancy has 3 haploid sets (69 chromosomes)
• It is a lethal aneuploidy.

Characteristics include:

• Multiple structural anomalies, such as CNS involving posterior fossa.
• Cardiac, renal, and extremities.
• Conseling and prenatal diagnosis are the same with trisomy 18 and 13.

Causes

• Heart defects, e.g. ventral septal defects.
• Cerebellar vermian agenesis.
• Myelomeningocele.
• Diaphragmatic hernia.
• Omphalocele.
• Imperforate anus.
• Renal anomalies, e.g. horseshoe kidney.
• Cranial and extremity abnormalities, e.g. prominent occiput, micrognathia, clenched hands with overlapping digits.
• Radial aplasia with hyperflexion of wrists.
• Rockerbottom or clubbed feet.
• Strawberry-shaped cranium.
• Wide cavum septum pellucidum.
• Choroid plexus cysts.