Genetic History and Trisomy

Genetic History

• Genetic counseling aims to identify individuals or couples at risk of having a child with chromosome abnormality, inherited conditions, or birth defects.
• Genetic counseling should ideally occur before conception.
• Major congenital anomalies are present in 3% of liveborn infants, or 1 in 160 newborns.
• Inquire about first-degree relatives (siblings, parents, offspring), second-degree relatives (nephews, nieces, aunts, uncles, grandparents), and third-degree relatives (first cousins, especially maternal).
• Advanced maternal age (AMA) and paternal sperm in the 6th and 7th decades are factors that increase risk

Autosomal Trisomy

• Autosomal trisomy involves having an extra copy of an autosomal chromosome
• Trisomy 21 is the most common autosomal trisomy

Trisomy 21

• Incidence of trisomy 21 is 1 in 800 live births
• Facial features of trisomy 21 include: brachycephaly, oblique palpebral fissures, epicanthal folds, broad nasal bridge, protruding tongue, small, low-set ears with an overlapping helix and a prominent antihelix, and iridial Brushfield spots
• Skeletal features of trisomy 21 include: broad, short fingers (brachymesophalangia), clinodactyly (incurving fifth finger resulting from an abnormality of the middle phalanx), a single flexion crease on the fifth digit, and wide space between the first two toes
• Cardiac defects, duodenal atresia, and neonatal hypotonia are common
• There is increased susceptibility to respiratory infections and leukemia
• Mean survival extends into the fifth decade
• Mean IQ is 25 to 70
• Relationship to maternal age is well known
• Mosaicism results in a higher IQ, occurring when only some cells in the body have an extra copy of chromosome 21, leading to a less severe presentation
• Women with Down syndrome are usually fertile, with a 30% chance of affected offspring
• Men with Down syndrome are always infertile

Trisomy 13

• Incidence of trisomy 13 is 1 in 20,000 live births
• Facial features of trisomy 13 include holoprosencephaly, eye anomalies (microphthalmia, anophthalmia, or coloboma), cleft lip and palate, and polydactyly
• Cardiac defects, cutaneous scalp defects, hemangiomata on the face or neck, low-set ears with an abnormal helix, and rocker-bottom feet (convex soles and protruding heels) also present
• Intrauterine and postnatal growth restriction
• Severe intellectual disability
• Survival beyond three years is rare and caused by nondisjunction (47, +13)

Trisomy 18

• Incidence of trisomy 18 is 1 in 8000 live births
• Facial features: microcephaly, prominent occiput, low-set and pointed fawnlike ears, micrognathia
• Skeletal anomalies: overlapping fingers (V over IV, II over III), short sternum, shield chest, narrow pelvis, limited thigh abduction or congenital hip dislocation, rocker-bottom feet with protrusion of the calcaneum, and a short dorsiflexed hallux (hammer toe)
• Cardiac defects, renal anomalies
• Intrauterine growth restriction, developmental disability
• Stillbirth is common
• Decreased fetal movement
• Survival is measured in months

Other Autosomal Trisomies

• Other autosomal trisomies usually end in miscarriage
• Trisomies 8, 9, 14, 16, and 22 can be detected in liveborns but with mosaism.
• All have some degree of intellectual disability, structural abnormalities, and IUGR

Autosomal Deletions and Duplications

• Only a portion of the chromosome is missing or deleted (deletions) or a portion is replicated (duplication)
• Severity of effects can vary greatly depending on genes involved and size of the deletion or duplication, with possible learning and intellectual disability, neurologic or behavior disorders, psychological disorders, and various congenital abnormalities

Common Deletion Syndromes

• Most are only detected by chromosomal microarray analysis, requiring a special test that's not found on normal karyotyping
• Most occur sporadically and are not associated with paternal or maternal age
• Recurrence risk is low (1%), but testing may be desired in future pregnancies due to the potential for germline mutation (egg and sperm cell)
• If a copy number variant is found in a parent, the risk to offspring is 50%

Wolf-Hirschhorn Syndrome

• The chromosome region is 4p16.3
• Clinical features are IUGR, failure to thrive, microcephaly, developmental delay, hypotonia, cognitive deficits, seizures, cardiac defects, and GU abnormalities

Cri du Chat Syndrome

• The chromosome region is 5p15.2
• Clinical features are microcephaly, SGA, hypotonia, catlike cry, and cardiac defects

Williams Syndrome

• The chromosome region is 7q11.23
• Clinical features are supravalvular aortic stenosis, hypercalcemia, developmental delay, mild to moderate intellectual disability, social personality, attention-deficit disorder, and female precocious puberty

Prader-Willi Syndrome

• The chromosome region is 15q11.2q13
• Clinical features are hypotonia, delayed development, short stature, small hands and feet, childhood obesity, learning disabilities, behavioral problems, and delayed puberty

Angelman Syndrome

• It has the same chromosome region as Prader-Willi (15q11.2q13)
• Clinical features are developmental delay, intellectual disability, impaired speech, gait ataxia, happy personality, seizures, and microcephaly

Smith-Magenis Syndrome

• The chromosome region is 17p11.2
• Clinical features are mild to moderate intellectual disability, delayed speech and language skills, behavioral problems, short stature, reduced sensitivity to pain and temperature, and ear and eye abnormalities

Alagille Syndrome

• The chromosome region is 20p12
• Clinical features are bile duct paucity, peripheral pulmonary artery stenosis, cardiac defects, vertebral and GU anomalies

DiGeorge Syndrome

• The chromosome region is 22q11.2
• Clinical features are cardiac defects, hypocalcemia, thymic hypoplasia, immune defect, renal and skeletal anomalies, delayed speech, learning difficulties, and psychological and behavioral problems

Sex Chromosome Abnormalities

Turner Syndrome

• It presents as Monosomy X (45,X)
• It occurs in 1 in 10,000 liveborn girls
• It accounts for 10% of first-trimester abortions
• The loss of the paternal sex chromosome occurs 80% of the time
• It is frequently a mosaicism
• Common features are primary ovarian failure, absent pubertal development, short stature, renal and cardiac,skeletal defects, and a low posterior hairline; adult-onset diseases include HTN, CAD, hypothyroidism, and type 2 DM
• Estrogen treatment can induce puberty/long-term hormone replacement
• Pregnancy may be achieved with a donor egg

Klinefelter Syndrome

• Presents as 1 IN 1000 males with two or more x chromosomes (47,XXY, 48XXXY, 49 XXXXY)
• Small testes, azoospermia, elevated FSH and LH
• Hypoplastic penis
• Intellectual disability is uncommon in the most common presentation 47,XXY but behavior problems and receptive language are common
• 48XXXY, 49XXXXY- intellectual disability,skeletal, trunk and craniofacial abnormalities

Polysomy X in Girls

• Occurs with 47,XXX or 49, XXXX
• Presents in 1 in 800 liveborn GIRLS
• Most have a normal reproductive system, therefore they have 50% risk of delivering infants with abnormal chromosomes since ½ of maternal gametes carry 24xx
• IQ is 10-15pts lower
• 48XXXX and 49XXXXX are intellectually disabled

Polysomy Y in Boys

• Presents with 47,XYY and 48XXYY
• Occurs in 1 in 1000 boys
• 47XYY is worse than 46xy, with tall stature and increased risk for learning disabilities, speech and language delay, and behavior and emotional disabilities
• Normal male phenotype and sexual development

Screening for Aneuploidy

• Noninvasive screening for chromosome disorders such as trisomy 21 and 18 routinely offered regardless of maternal age, but screening is not equivalent to testing which gives a definitive answer
• Cell-free DNA analysis can can be performed as early as 10 weeks however negative results do NOT ensure an unaffected pregnancy.
• It has high sensitivity for trisomy 13, 18 and 21 with rate of false positives at less than 1%
• Positive results still need to be confirmed by diagnostic testing

First Trimester Screening

• First-trimester screening occurs between 11-14 weeks
• Combo of biochemical markers, pregnancy associated plasma protein (PAAP-A) and b-HCG with ultrasound of nuchal translucency (NT) which is the space behind fetal neck
• Trisomy 21 presents with decreased PAPP-A, and increased bhCG and NT
• NT greater than 4mm is always associated with abnormal noninvasive screen and requires diagnostic testing
• NT greater than 3.3mm and normal fetal karyotype require follow up with targeted ultrasounds in 2nd trimester with fetal echo to rule outcaridiac abnormalities.

Second Trimester Serum Screening

• Second trimester serum screening occurs between 15-22 weeks
• Quad screen evaluates AFP, hCG, unconjugated estriol (uE3), and dimeric inhibin A
• Detecting trisomy 21 is 75% in women under 35 and 80% in women >35. False positive rate is 5%, AFP and uE3 reduced, while detection for trisomy 18 uses only the first three markers, therefore detection rate is 70%, AFP, uE3 hCG are reduced
• False positives can occur if maternal weight, gestational age, ethnicity, diabetes mellitus, and number of fetuses
• sequential screening begins with 1st trimester screening, if risk is high, genetic counseling and diagnostic testing are offered, if results are low, or moderate, offered 2nd trimester screening to determine final risk, when risk is low in the 1st trimester no further testing is recommended.

Aneuploidy Screening in Multiple Gestation

• Using multiple serum markers to screen for down syndrome is less sensitive in twin pregnancies
• Cell-free DNA is a better alternative for screening

Ultrasound Screening for Aneuploidy

• NT thickness is increased and associated with trisomy 21 with nasal bone length, short femur or humerus present plus echogenic foci in the heart, echogenic bowel and pyelectasis, with an overall high rate of false positives
• Diagnostic Strategy for Detecting Chromosome Abnormalities involves a positive screening test or abnormal sonogram followed by recommending an invasive diagnostic procedure
• Indications for prenatal cytogenetic testing are that ACOG recommends that all women regardless of age be offered screening or diagnostic testing for aneuploidy including the option of a CMA
• Assisted reproduction through intracytoplasmic sperm injection
• Previous child with a chromosome abnormality
• Parental chromosome rearrangements

Cytogenomic Testing and Chromosome Microarrays

• It is recommended to use cytogenic/ cytogenomic testing when using a banded karyotype while chromosome micro arrays, Fluorescence in Situ hybridization-FISH examines specific chromosome region or rapidly screen for aneuploidy useful when parent with known deletion or couple w/previous affected child request test for just that region available for diagnostics on the same day.

Accuracy of Prenatal Cytogenetic Diagnosis

• Cells may not grow or be insufficient for analysis from amnio or CVS sample, which includes maternal cell contamination
• Abnormality could be in placental tissue not fetus which should be suspected in mosiacism or when abnormal karotype does not correlate with normal ultrasound

Single Gene or Meldelian Disorders

• Carrier screening for hereditable disorders is performed to determine weather and individual has mutation in one of the two copies (hetrozygous carrier) of the gene of interest with risk of having affected offspring is 25% for both parents are carriers for a autosomal recessive disorder

Ashkenazi Jewish Genetic Diseases and Hemoglobinopathies

• Offer screening to all jewish people while Thalassemia is more prevalent in S.E asian, african, westindian, Mediterranean, asian and middle eastern
• ACOG recommends cbc and hemoblobin electrophoresis for couples at risk while other common disorders are Cystic fibrosis for Whites, N.E european, and Ashkenazi jewish with Spinal muscular atrophy being more progressive particularly in Whites/hispanic population, while the screening for Fragile X syndrome is recommended for women w/family hx of fragile X or unexplained cognitive impairment, autism, tremor/ataxia disorder, or unexplained premature ovarian insufficiency.

Newborn Screening and Molecular Approach to Prenatal Diagnosis

• Neonatal screening is mandated in each states with Parents may decline testing & in some states are required consent for DHH recommending screening for a core of 34 conditions & inborn errors of metabolism amenable to treatment ###Molecular approach to prenatal diagnosis of single gene disorders involves using a molecular approach while General testing for these can be done with whole exome sequencing which focuses on exons or protein coding regions of the genome but should not be recommended for routine offering but only for select cases.

Procedures for Prenatal Genetic Diagnosis

• Amniocentesis performed after 15 weeks however early (before 14 weeks) avoiding due to higher pregnancy loss, AF leakage, culture failures, talipes equinovarus with amniocentesis in twin pregnancies using US so the same sac is not used more than once
• Chorionic villus sampling allows genetic diagnosis in the first trimester of pregnancy is performed between 10-13 weeks by transcervical or transabdominal approach. Key safety issues are critical is counseling twin pregnancies for prenatal diagnosis is to establish chronicity

Invasive diagnostic testing

• Consider Invasive diagnostic testing in women with hepatitis B, hepatitis C, and HIV while Invasive prenatal testing can be carried out but to educate that there is limited data on transmission.

Fetal Blood Sampling and Preimplantation Genetic Testing

-Fetal blood sampling uses US directed for percutaneous umbilical blood sampling (PUBS) or cordocentesis when most common indications are fetal malformation during the 2nd and 3rd trimester Preimplantation Genetic Testing involves first testing embryo status w/in 6 days of conception where Novel indications addressed only by preimplantation genetic testing include avoiding pregnancy termination such as PGT is the only prenatal genetic diagnostic approach available for couples who wish to avoid an abnormal fetus though they are opposed to termination Viability is therefore reduced by 10% when a single blastomere is removed

###Gestational Age Determination - Prenatal Care

• Pregnancy calendar should determine Human pregnancy duration: 280 days or 40 weeks from LMP with Naegele's rule requiring adding 7 days and subtracting 3 months tolst day of LMP
• Clinical parameters when assessing patients involves measuring Uterine size which correlates well with gestational age though Ultrasound used to confirm pregnancy, determine viability, estimate gestational age, screen for aneuploidy such as the assesssment , survey of anatomy (16-18 weeks) and assessment of cervical length

Pregnancy Failure - Prenatal Care early or late assessment involving the following

_ diagnosis when the Gold standard is performing Ultrasound and then, performing Laboratory findings - which should follow-up with (if US findings equivical) serial serum b-hCG measurements that would fail to increase appropriately _Signs and symptoms - absence of fetal movements that are noted and felt by mother

• Complications - risk Disseminated Intravascular Coagulopathy (DIC) is rare sequelae to an Intruterine Fetal Demise (IUFD)

Initial Prenatal Assessment

• Involves gathering current Obstetric history regarding current/previous symptoms, previous pregnancy outcomes and performing medical/ surgical examination and collecting family history to form patient pedigree though mainly Social history is documented with hx of alcohol & tobacco, recreational/illicit/IV drugs, as well as any other potentially harmful substance exposures along with a performing physical assessment for any anatomical abnorality

Laboratoty Examinations During Prenatal Care

_Initial blood test - involves testing CBC, Blood type and Rh screen, antibody screen, STIs such as RPR or HepB followed by testing HIV/Rubella antibody/varicella

• Screening - is performed after the1st trimester and involves the fetal nuchal translucency + maternal testing of maternal analysis of pregnancy-associated plasma protein A (PAPP-A), and free or total b-hCG to screen for trisomy (21, 18, & 13).
• Serum a fetoprotein (AFP) needs to still be drawn around 15-18 weeks gestation.

Other Important Tests - Prenatal Care

__Urine testing - performs urinalysis + culture on initial as 2-12% of pregnant women have an asymptomatic urinary tract infection __Papanicolaou Smear PAP - performed at initial visit in women over 21 unless patient has negative screening within last 3 years __Sexually transmitted disease assessment and Testing Syphilis

Routine prenatal assessment

Involves Routine visits which are frequency depends on gestation, mother's condition, and fetal complications through: _Maternal weight gain as underweight patients should gain more weight & obese patients should gain less weight _Blood pressure to decreases/determine vascular compromise

• Fetal size and position measured thorugh Bony pelvis - should be performed at initial OB visit

Common Complaints during prenatal care

• -Ptyalism requires the assessment of Thyroid function when determining potential causes for such _Urinary frequency can also be assocaited with renal infection when it causes Dysuria & hematuria _ Varicose veins needs to be managed when the patient TX: elevate lower legs, thigh-high compression stockings and ruleded out from th use of DVT

Laboratory Evaluation - Prenatal

• Gestational diabetes screening is essential =Antibody testing - initial and repeat for unsensitized, D-negative patients between 28-29 weeks

Complications during perinatal care

_Bathing & swimming are fine, but water >100'F in 1st trimester is linked to neural tube defects (hot tubs).

• Medications - teratogen: toxin, drug, or biological agent that can harm a fetus; +Nicotine and cigarette smoking - increases risk of IUGR, placenta previa, placental abruption, preterm birth, SGA, SIDS, and perinatal mortality. Approx 20-50% of pregnant women smoke or exposed to passive smoking. +Alcohol increases Fetal Alcohol Syndrome and has been found in women who consumed > 2oz daily with incidents of 1 in 600 to 1 in 1500 live births

Pulminary and Cardiac Changes

Anatomic changes occur and include Uterine enlargement & diaphragmatic elevation but the changes result in an increase in the lower thoracic diameter by approximately 2 cm and the thoracic circumference Lung Volumes and capacity undergo changes are affected, and with Respiration, Increased Progesterone appear to have a critical role in hyperventilation to avoid hypervolemai

Renal and Gastroinstenial Changes

__During pregnancy the length of the kidneys increase by 1-1.5cm, a __Intestinal transit time are decreased in the 2nd and 3rd trimeste Gallbladder Emptying of the gallbladder is slowed and often incomplete

Hematological Changes and Placental Transport

_plasma volume accounts for anemia in pregnancy+Supplementation needed due to enhance erythropoiesis increases utilization of iron causing to an increase total blood leukocyte woth the Placenta expressing P-glycoprotein actively to keep Drugs are lower in the fetal circulation than in the maternal circulation

Placenta Secretions - Hormones

hCG- is a glycoprotein that helps in maintaining early pregnancy and acts Immunosuppressant Is the main precursor towards steroid synthesis and protein growth Factors

• There are four pregnancy associated plasma proteins (PAPPs) - all proteins are produced by the placenta and/or decidua with and function to maintain blood supply and prevent clotting

Anotomic Disorders

_ Many or Nearly all monochorionic twin placentas undergo an anastomosis between the vessels

Placenta Accreta - Previas with Various Cord and Uterine Abnormalities

_Involves performing a placental invasion with possible in surrounding tissues such as the Bladder The vessels twist, then Expand by forming tube before differentiating and The cord allows is the attachment site before fusing.