[01.03b] Principles of Genetics & Overview of Genetic Pathology (Part 2) V2

Most common chromosomal disorder

What is Trisomy 21 also known as?

Major cause of intellectual disabilities or mental retardation

What is Trisomy 21 a significant cause of?

IQ of 25-50

What is the typical IQ range for individuals with Trisomy 21?

Trisomy 13 and Trisomy 18

Which other trisomies have features similar to Trisomy 21?

Meiotic nondisjunction

What is the primary cause of Trisomy 21 in 95% of cases?

Parents of such children have a normal karyotype and are normal in all respects

What is true about the karyotype of parents of children with Trisomy 21 due to meiotic nondisjunction?

Maternal age

What factor strongly influences the occurrence of Trisomy 21?

1 in 1550 live births

What is the incidence of Trisomy 21 for women under age 20?

1 in 25 live births

What is the incidence of Trisomy 21 for mothers over age 45?

35 years old

What is the current average age of mothers, according to obstetricians, relating to Trisomy 21 risk?

Extra chromosome is maternal in origin, located in the ovum

From which parent and gamete does the extra chromosome in Trisomy 21 usually originate?

Elderly primigravids

What term describes first-time pregnant women with a high likelihood of having children with conditions like Down Syndrome?

Women over 32 years old

At what age are women currently considered elderly primigravids?

4%

What percentage of Trisomy 21 cases arise via Robertsonian translocation?

Familial in origin

What is the origin of Trisomy 21 cases caused by Robertsonian translocation?

Robertsonian translocation and ring chromosome

What are considered two of the worst types of translocation?

1%

What percentage of Trisomy 21 cases are mosaic?

Having a mixture of cells with 46 or 47 chromosomes

What defines a mosaic case of Trisomy 21?

Milder phenotypic changes

What are the phenotypic effects in mosaic cases of Trisomy 21?

Flat facial profile, oblique palpebral fissures, epicanthic folds

Name three diagnostic clinical features of Trisomy 21 visible at birth.

40%

What percentage of individuals with Trisomy 21 have congenital heart disease?

Endocardial cushion, atrial septal defect (ASD), ventricular septal defect (VSD), valvular malformations

Name some specific types of congenital heart disease associated with Trisomy 21.

Immediate physical examination

What immediate action must be performed upon birth of an infant with Trisomy 21 for early detection of heart defects?

10-20 fold risk of acute leukemia

What is the increased risk for acute leukemia in Trisomy 21 patients?

Acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML)

Name two types of acute leukemia seen in Trisomy 21 patients.

Very high risk of hematologic malignancy

What is the overall risk for hematologic malignancy in Trisomy 21?

Alzheimer’s Disease

Individuals with Trisomy 21 older than 40 years old have a higher risk of developing what neuropathologic change?

Abnormal Immune Response

What kind of immune response is characteristic of Trisomy 21, predisposing individuals to serious infections?

Acute megakaryoblastic leukemia

According to Robbins & Cotran (2021), what specific type of leukemia is associated with Trisomy 21, as opposed to "megaloblastic"?

FISH (Fluorescence in situ hybridization) with chromosome 21-specific probes

What is the fastest way to diagnose Trisomy 21?

Under dark light, probes reveal the extra copy of chromosome 21

How does FISH confirm the diagnosis of Trisomy 21?

Karyotyping

What is the classical method for diagnosing a patient with Trisomy 21?

Epicanthic folds, flat facial profile, abundant neck skin, Simian crease, congenital heart defects, intestinal stenosis, predisposition to leukemia, hypotonia of the legs

Name at least five common manifestations of Trisomy 21.

1 horizontal line traversing the palm

What is a Simian crease?

2 creases

How many creases are normally found on the palm?

Trisomy 21 type and Mosaic type

What are the two common karyotypes for Down Syndrome?

47,XX,+21 or 47,XY,+21

What are the specific karyotypes for Trisomy 21 type in females and males, respectively?

Proportion of cells that are normal karyotype and another proportion that have the abnormal karyotype

What defines the mosaic type karyotype for Trisomy 21?

Increased in maternal age

What factor is associated with an increased risk of Trisomy 18?

More severe malformation

How do malformations in Trisomy 18 compare in severity to those in Trisomy 21?

1/8,000 live births

What is the incidence of Trisomy 18?

Meiotic nondisjunction

What is the cause of Trisomy 18?

Prominent occiput, microcephaly, mental retardation, micrognathia, low set ears, short neck, overlapping fingers, hip abduction, Rockerbottom feet, heart defect, renal malformation (horseshoe kidney)

Name at least five characteristic features of Trisomy 18.

Feet are extended; Resembles a rocking chair

Describe "Rockerbottom feet" seen in Trisomy 18.

Rarely survive beyond 1 year

What is the typical survival prognosis for individuals with Trisomy 18?

1/15,000 live births

What is the incidence of Trisomy 13?

Meiotic nondisjunction

What is the cause of Trisomy 13?

Microcephaly and mental retardation, cleft lip and cleft palate, polydactyly (extra digits), cardiac defect, rockerbottom feet, umbilical hernia

Name at least three features of Trisomy 13.

Extra digits

What does polydactyly mean?

Non-compatible with life; often an early death

What is the survival prognosis for individuals with Trisomy 13?

Small deletion of band q11.2 on the long arm of chromosome 22

What is the genetic basis of Chromosome 22Q11.2 Deletion Syndrome?

Congenital heart defects, abnormalities of the palate, facial dysmorphism, developmental delay, T-cell immunodeficiency, hypocalcemia

Name some variable clinical features of Chromosome 22Q11.2 Deletion Syndrome.

DiGeorge Syndrome and Velocardiofacial syndrome

What are the two distinct manifestations of Chromosome 22Q11.2 Deletion Syndrome?

Thymic hypoplasia

What is the hallmark of DiGeorge Syndrome that leads to T-cell immunodeficiency?

Underdeveloped thymus results to disrupted T-cell production, making patient prone to diseases

What is the consequence of thymic hypoplasia?

Parathyroid hypoplasia

What condition in DiGeorge Syndrome leads to hypocalcemia?

Cardiac malformations, atopic disorders, autoimmunity

Besides hypoplasia of the thymus and parathyroid, what other issues are associated with DiGeorge Syndrome?

Facial dysmorphism, cleft palate, cardiovascular anomalies, learning disabilities

What are the key features of Velocardiofacial syndrome?

High risk for psychotic illness (Schizophrenia 25%, bipolar disorder); ADHD (30-35%)

What significant psychiatric risks are associated with Chromosome 22Q11.2 Deletion Syndrome?

Detection of deletion by FISH

How is Chromosome 22Q11.2 Deletion Syndrome diagnosed?

Look for loss of signal

What is observed during FISH diagnosis for Chromosome 22Q11.2 Deletion Syndrome?

Broad nose, epicanthal folds, small chin, downward mouth angle, prominent ears

Name characteristics of the typical facial appearance in Velocardiofacial Syndrome.

CATCH 22

What mnemonic is used for DiGeorge Syndrome?

Cardiac abnormality (especially Fallot’s Tetralogy), Abnormal facial features, Thymic hypoplasia, Cleft palate, Hypocalcemia, 22 for Chromosome 22Q11.2

What does the CATCH 22 mnemonic represent?

More common and better tolerated than autosomal aberrations

How do cytogenetic disorders involving sex chromosomes compare to those involving autosomes?

Lyonization

What is the process where all but one X chromosome is inactivated?

Manifestations are usually normal

What is the usual outcome despite X chromosome inactivation?

Normal X chromosome manifests while the abnormal X chromosome is inactivated

In females, what happens to the normal and abnormal X chromosomes regarding manifestation?

Less of a problem

Is having XX chromosomes generally more or less problematic for females in sex chromosome disorders?

Only 1 is working

Even with multiple copies of the X chromosome, how many are typically genetically active?

Modest amount of genetic material

What amount of genetic material is carried by the Y chromosome?

Mary Lyon in 1961

Who formulated the Lyon Hypothesis and in what year?

Only one of the X chromosomes is genetically active

What is the core principle of the Lyon Hypothesis?

Barr body

What is the inactivated X chromosome called, which undergoes heteropyknosis?

Special stains

What is needed to view Barr bodies under a light microscope?

Random at day 5.5 of embryonic life

When and how does the inactivation of either the maternal or paternal X chromosome occur?

Inactivation of the same X chromosome persists in all the cells derived from each precursor cell

What happens to the inactivation pattern in daughter cells?

Many X chromosomes escape gene inactivation

What have recent studies shown regarding X chromosome inactivation?

Normal X chromosome manifestations with some abnormal ones

What can result when X chromosomes escape gene inactivation?

Mostly affects females

Which sex is primarily affected by the consequences of X chromosomes escaping gene inactivation?

Single Y chromosome

What chromosome determines male sex?

SRY (sex determining region Y gene)

What specific gene on the Y chromosome is responsible for sex determination?

All Y chromosome deletions are associated with azoospermia

What is the consequence of all Y chromosome deletions?

Infertile

What is a likely consequence for a patient with mutations in the Y chromosome, regarding passing on Y-linked abnormalities?

Causes subtle, chronic problems related to sexual development and fertility; difficult to diagnose at birth, recognized at puberty

What are the general features and typical diagnosis time for sex chromosome disorders?

Secondary sex characteristics are expected to arise in puberty, but they don’t

What is a key observation that often leads to diagnosis of sex chromosome disorders at puberty?

Greater number of X chromosomes, greater likelihood of mental retardation

What correlation exists between the number of X chromosomes and intellectual disability?

Klinefelter Syndrome and Turner Syndrome

What are two important sex chromosome disorders mentioned?

One of the most frequent forms of sex chromosomal disorders

How is Klinefelter Syndrome described in terms of frequency among sex chromosomal disorders?

Most common cause of hypogonadism in males

What is Klinefelter Syndrome the most common cause of in males?

Usually 2 X and 1 Y hence genetically male

What is the typical genetic makeup of an individual with Klinefelter Syndrome?

2 or more X chromosomes; 1 or more Y chromosomes

What are the chromosomal requirements for Klinefelter Syndrome?

The more Y, the more aggressive the patient is

What behavioral trait is associated with an increased number of Y chromosomes in Klinefelter Syndrome?

Usually diagnosed and seen during puberty

When is Klinefelter Syndrome typically diagnosed?

Elongated body, eunuchoid body habitus with long legs; small atrophic testes, small penis; lack of secondary male characteristics; gynecomastia; lower IQ; increased FSH & estradiol; decreased testosterone levels; mitral valve prolapse; osteoporosis

Name at least five distinctive clinical features of Klinefelter Syndrome.

Males seeming to have female bodily features

What does "eunuchoid" habitus refer to?

Hypogonadism

What is a consistent finding in Klinefelter Syndrome?

Important genetic cause of reduced spermatogenesis and male infertility

What reproductive issues are directly linked to Klinefelter Syndrome?

Atrophic testicular tubules, prominent Leydig cells

Describe the histologic appearance of testes in Klinefelter Syndrome.

High risk for breast cancer, extragonadal germ cell tumors and autoimmune diseases (SLE)

What cancer and autoimmune risks are increased in Klinefelter Syndrome?