Chapter 14: Genetics

Mendelian inheritance · Chromosomal disorders · Mitochondrial inheritance · Imprinting · Genetic testing (karyotype, FISH, microarray, NGS) · Clinical genetics · Dysmorphology · Syndrome diagnosis · Genetic counseling · Forfar & Arneil's Pediatrics
📌 Core principles: Genetics fundamental to pediatric disease – single gene (autosomal dominant/recessive, X‑linked), chromosomal (aneuploidy, deletions/duplications), mitochondrial (maternal inheritance), imprinting disorders. Genetic testing: karyotype, FISH, CMA, NGS. Dysmorphology: identify patterns, syndrome diagnosis. Genetic counseling essential for families.

📖 Core summary: genetics in pediatrics

🧬 Mendelian inheritance
Autosomal dominant (AD): affected parent → 50% risk (e.g., NF1, achondroplasia). Autosomal recessive (AR): carrier parents, 25% risk (CF, PKU). X‑linked recessive (XL): males affected, females carriers (DMD, hemophilia).
🧬 Chromosomal disorders
Numerical: trisomy 21 (Down), 18 (Edwards), 13 (Patau), Turner (45,X), Klinefelter (47,XXY). Structural: deletions (22q11, 7q11.23 – Williams), duplications, translocations. Detected by karyotype, FISH, CMA.
🧬 Imprinting & uniparental disomy (UPD)
Imprinted genes: Prader‑Willi (paternal deletion), Angelman (maternal deletion). UPD when both homologues from one parent.
🧬 Mitochondrial disorders
Maternal inheritance (mtDNA). Heteroplasmy. Examples: MELAS, MERRF, Leigh syndrome. Variable expression.
🔬 Genetic testing
Karyotype (numerical/structural >5‑10 Mb). FISH (targeted). Chromosomal microarray (CMA) – copy number variants (deletions/duplications). Next‑generation sequencing (NGS) – gene panels, exome, genome.
🧑‍⚕️ Dysmorphology & genetic counseling
Dysmorphology: systematic evaluation of minor anomalies, patterns. Syndrome diagnosis vs association/sequence. Genetic counseling: recurrence risk, testing options, prenatal diagnosis, psychosocial support.
📊 Key red flags for genetic evaluation: Multiple congenital anomalies, developmental delay/intellectual disability, dysmorphic features, growth abnormalities, family history of genetic disorder, consanguinity.

🔍 Approach to genetic evaluation in children

1
Detailed family history (3 generations) – Draw pedigree. Consanguinity, miscarriages, stillbirths, multiple affected individuals, age of onset, pattern consistent with AD/AR/XL/mitochondrial.
2
Dysmorphology examination – Systematic assessment: head (shape, size, hair whorls), face (hypertelorism, low‑set ears, micrognathia, palpebral fissures, philtrum), hands (brachydactyly, single palmar crease), feet, skin, genitals.
3
Anthropometry & growth – Plot height, weight, head circumference on growth charts. Note macrocephaly, microcephaly, overgrowth, short stature, asymmetric growth.
4
Choose appropriate genetic test – Karyotype (suspected aneuploidy). FISH (targeted deletion/duplication, e.g., 22q11). CMA (developmental delay, multiple anomalies, autism). Gene panel/exome for specific phenotypes.
5
Genetic counseling & recurrence risk – Explain inheritance, testing options, prenatal diagnosis. Psychosocial support, connect to family support groups.

📋 Stepwise management of genetic disorders

1
Establish diagnosis – Clinical evaluation + appropriate genetic testing. Confirm with molecular testing where available.
2
Medical management of associated conditions – Screen for comorbid conditions (e.g., CHD in 22q11, thyroid in Down, scoliosis in NF1). Multidisciplinary team.
3
Surveillance & preventive care – Regular monitoring of growth, development, hearing, vision, thyroid, cardiac, spine as per syndrome guidelines.
4
Genetic counseling for family – Recurrence risk, prenatal testing options (CVS, amniocentesis, NIPT). Carrier testing for relatives.
5
Support & resources – Refer to clinical genetics, early intervention, therapy (PT/OT/SLP). Patient advocacy groups (e.g., NF Network, Down Syndrome Association).
6
Transition to adult care – Plan for transfer to adult genetics/appropriate specialists. Address reproductive choices.
⚡ Key reminder: Chromosomal microarray (CMA) is first‑tier test for unexplained developmental delay/intellectual disability, multiple anomalies, autism spectrum disorder (detects deletions/duplications not seen on karyotype).

🧠 Reflex prompts – genetics high‑yield concepts

🧬 3 generation family history – male‑to‑male transmission. Which inheritance pattern?
Autosomal dominant. X‑linked recessive cannot have male‑to‑male transmission.
🧬 Child with developmental delay, coarse facies, hepatosplenomegaly, dysostosis multiplex.
Mucopolysaccharidosis (AR). Enzyme assay diagnostic.
🧬 Newborn with hypotonia, poor feeding, cryptorchidism, small hands/feet. Later hyperphagia.
Prader‑Willi syndrome (paternal deletion/maternal UPD). Methylation analysis.
🧬 Which genetic test for suspected 22q11.2 deletion (DiGeorge)?
FISH (targeted) or chromosomal microarray (CMA).
🧬 Mitochondrial disorder – inheritance pattern?
Maternal inheritance. All children of affected female may be affected; affected male does not transmit.
🧬 Consanguineous parents, child with AR condition. Recurrence risk?
25% for each pregnancy. Carrier frequency increased in consanguineous families.