Med Gene Week3

Pediatric Development + Neurogenetic Testing

Developmental Milestones Categories (4)

These are abilities that most children can achieve by a certain age

1. Physical (gross and fine motor skills)

2. Communication milestones (language and nonverbal

communication)

3. Cognitive

4. Social/emotional

Developmental delays

There is a significant delay in a particular developmental

milestone

Global Developmental Delay (GDD)

There is a significant delay in 2 or more developmental domains.

Diagnosis is reserved for younger children (<5 years), and GDD has a strong correlation with intellectual disability later in life.

Intellectual disability (ID)

Significant limitations in both

1. Intellectual functioning (IQ test) AND

2. Adaptive behavior (conceptual, social, and practical adaptive skills)

Diagnose only happens when the child is older than ~5 years of age (for reliability of the standardize tests)

ID is prevalent in 1-3% of the population

Syndromic ID

Type of intellectual disability that occurs as part of a larger syndrome and involves other medical and/or behavioral symptoms.

Genetic testing for GDD/ID

There are first- and second-tier tests (changes according to new guidelines)

Tier 1: Chromosomal microarray (CMA); Whole exome sequencing/whole genome sequencing

Tier 2: Fragile X testing; Methylation studies

Chromosomal Microarray Analysis (CMA)

High-resolution genetic test that detects tiny extra or missing pieces of DNA (deletions and/or duplications), known as copy number variants (CNV).

What it misses: Balanced chromosome rearrangements (where no DNA is gained or lost) or single-gene point mutations.

Fragile X Testing

Repeat analysis of CGG repeats in the FMR1 gene to determine if someone has fragile X syndrome

Gene Panels

Next-generation sequencing and deletion/duplication analysis to identify variants within a specific list of genes

Exome/Genome Sequencing (WES/WGS)

Next-generation sequencing and deletion/duplication analysis to identify variants within the exome or genome

Single Gene Analysis

Identifying variants in single gene(s) either through repeat analysis or sequence analysis based on specific clinical features (i.e. fragile X, MECP2)

Intraventricular Hemorrhage (IVH)

Condition that occurs when there is bleeding in the fluid-filled ventricles inside the brain.

The smaller and more premature the infant, the higher the risk.

Severe bleeding often leads to developmental delays, intellectual

disability, and problems controlling movement.

Fetal alcohol spectrum disorder (FASD)

Wide range of physical, behavioral, and cognitive impairments that occur when a fetus is exposed to alcohol before birth.

Symptoms include growth deficiency, microcephaly, developmental delays, intellectual disability, and facial dysmorphism

Maternal Phenylketonuria (PKU)

A metabolic genetic disorder characterized by increased levels of an amino acid called phenylalanine in the blood.

Symptoms may include intellectual disability, behavior issues, and a musty odor in the urine.

Note: These symptoms can be avoided by restricting foods high in phenylalanine, such as meat, nuts, and artificial sweeteners.

Teratogens

A substance that causes an abnormality following fetal

exposure during pregnancy.

Examples include medications, industrial chemicals, environmental

contaminants, physical agents, infections, and maternal disease

Can cause approximately 5% of congenital anomalies

Autism spectrum disorder (ASD)

Neurological and developmental disorder that affects how individuals interact with others, communicate, learn, and behave.

Genetic Testing for Isolated ASD

Karyotype (chromosome analysis): 3% diagnostic yield

• Rarely recommended as a first-tier test unless there is concern or a chromosome aneuploidy (Down syndrome) or a history suggestive of chromosomal rearrangements

CMA: 8-21% diagnostic yield

• Replaced karyotype as a first-tier test

Whole exome sequencing and whole genome sequencing

Syndromic ASD

An ASD linked to a recognized medical condition or single-gene genetic syndrome. It accounts for about 25% of all autism cases.

Most commonly associated with: Fragile X Syndrome, PTEN, and Rett

Hypotonia

Low muscle tone → little resistance, which can cause a “floppy”

appearance in infants.

Can be generic or present in a severe neonatal form.

Disorders that involve severe hypotonia: Myotonic Dystrophy, Prader-Willi Syndrome, Spinal Muscular Atrophy

Fragile X Syndrome

Most common single-gene cause of ID and ASD, caused by lack of FMRP protein produced by FMR1 gene due to expansion of CGG nucleotides in gene (over 200 causes syndrome).

Inheritance is X-linked dominant.

Symptoms are less severe in females than males.

Some symptoms are delayed development, seizures, long and narrow faces, large ears, macrocephaly, autism, behavioral issues

22q11.2 Deletion Syndrome (DiGeorge Syndrome)

Some symptoms are cardiac defects, palatal anomalies, low calcium, immunodeficiencies, renal anomalies, ear dysmorphology, hooded eyelids, prominent nasal root, bulbous nasal tip

Williams Syndrome

Caused by deletion at 7q11.23.

Some symptoms are cardiovascular disease, feeding difficulties, endocrine abnormalities, elevated calcium, hypotonia, joint hypermobility, over-friendly behavior, periorbital fullness, long philtrum, wide mouth

Smith-Magenis Syndrome

Caused by deletion at 17p11.2.

Some symptoms are behavioral abnormalities, self-injurous behavior, sleep disturbances, child-onset obesity, distinctive facial features, congenital defects

Prader-Willi Syndrome

Imprinting syndrome resulting from absence of paternally expressed genes in 15q11-13 imprinted region.

Some symptoms are hypotonia, feeding difficulties in infancy, excessive and uncontrolled eating later in life, obesity later in life, behavioral problems, short stature

Angelman Syndrome

Imprinting syndrome resulting from absence of maternally expressed genes in 15q11-13 imprinted region.

Some symptoms are happy demeanor, ataxia, tremors, seizures, microcephaly

Wolf-Hirschhorn Syndrome

Caused by deletions in 4p region.

Some symptoms are microcephaly, growth restriction, widely spaced eyes, arched eyebrows, epicanthal folds, short philtrum, Greek warrior appearance of nose.

Cri du Chat Syndrome

Caused by deletions in 5p region.

Some symptoms are intrauterine growth restriction, postnatal growth deficiency, round face, epicanthal folds, micrognathia, low-set ears, single palmar crease, congenital heart defect

PTEN Hamartoma Tumor Syndrome

A spectrum of overlapping disorders, including Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN-related Proteus Syndrome, and PTEN-related Proteus-like Syndrome.

Caused by pathogenic variants in PTEN inherited in an autosomal dominant manner.

Cowden Syndrome

A multiple hamartoma syndrome associated with high risk of thyroid, breast, and endometrial cancers.

Some other symptoms are colon polyps, trichilemmomas, papillomatous papules, acral and plantar keratoses, macrocephaly, dolichocephaly, ASD, developmental delay, and ID

Bannayan-Riley-Ruvalcaba Syndrome

Some symptoms are macrocephaly, intestinal hamartomatous polyposis, lipomas, pigmented macules, low birth weight, developmental delay, ID, ASD, muscle issues, joint hyperextensibility, pectus excavatum, scoliosis, and higher risk of thyroid, breast, and endometrial cancers

PTEN-related Proteus Syndrome

Some symptoms are congenital malformations, hamartomatous overgrowth of multiple tissues, moles, tumors, pulmonary issues, predisposition to deep vein thrombosis and pulmonary embolism. there are little to no symptoms at birth.

Symptoms progress rapidly through childhood causing severe overgrowth and disfigurement.

PTEN-related Proteus-like Syndrome

Similar to Proteus syndrome but describes individuals with many clinical features of it that do not meet diagnostic criteria

Rett Syndrome

Caused by pathogenic variants in MECP2 gene.

Inherited in X-linked dominant fashion.

Some symptoms are developmental regression, slow head growth, gait abnormalities, seizures, hand stereotypies, loss of purposeful hand skills, absence of speech, high-pitched crying, cold extremities, irregular breathing, ASD.