Clinical Genetics: Chromosomal and imprinting disorders

• Mechanisms: How Chromosomal Abnormalities Arise | Translocations and Structural Rearrangements
• Autosomal trisomies: Down Syndrome (Trisomy 21) | Down Syndrome - Adult Health | Edwards (Trisomy 18) and Patau (Trisomy 13) Syndromes
• Sex chromosomes: Turner Syndrome (45,X) | Klinefelter Syndrome (47,XXY) | Other Sex Chromosome Variations and DSD
• Microdeletions: 22q11.2 Deletion Syndrome | Williams Syndrome | Other Microdeletion Syndromes
• Imprinting: Prader–Willi Syndrome | Angelman Syndrome | Beckwith–Wiedemann and Silver–Russell Syndromes
• Revision: Chromosomal Disorders at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧬 Chromosomal and imprinting disorders - page 3 of the Clinical Genetics chapter. Chromosomal abnormalities are found in about half of first-trimester miscarriages and in a significant number of children with learning disability and congenital anomalies. The common ones - Down, Turner, Klinefelter and 22q11.2 deletion syndromes - affect people across their lifespan, so adult physicians need to know their long-term health problems as well as paediatricians do.
Your four questions for every suspected chromosomal disorder: What pattern of features is present? Which test will confirm it - QF-PCR, karyotype, microarray or methylation? Is there a parental rearrangement that changes recurrence risk? What lifelong surveillance does this person need?

How Chromosomal Abnormalities Arise

• Aneuploidy - an abnormal number of chromosomes (trisomy - one extra; monosomy - one missing).
  • Usually from non-disjunction - chromosomes fail to separate during meiosis, most often in the mother's egg (meiosis I).
  • Risk rises with maternal age (especially over 35) - trisomies 21, 18 and 13 and 47,XXY.
  • Most aneuploidies are lethal early in pregnancy; only trisomies 13, 18, 21 and sex chromosome aneuploidies commonly survive to birth.
• Polyploidy - a whole extra set (triploidy - 69 chromosomes) - causes miscarriage, molar pregnancy (partial mole) or severe fetal growth restriction.
• Mosaicism - two cell lines (e.g. 46,XX/47,XX,+21) from non-disjunction after fertilisation - often milder features.
• Structural abnormalities - deletions, duplications, translocations, inversions, ring chromosomes, isochromosomes.
• Microdeletions and microduplications - too small to see on a karyotype; detected by microarray; often arise de novo (from non-allelic recombination between repeated sequences).
• Notation - e.g. 47,XX,+21 (female with trisomy 21); 45,X (Turner); 46,XY,del(22)(q11.2); 45,XX,der(14;21) (balanced Robertsonian carrier).

Translocations and Structural Rearrangements

• Reciprocal translocation - two chromosomes swap segments.
  • Balanced carriers (about 1 in 500 people) are usually healthy, but risk miscarriage, infertility and children with unbalanced chromosomes (learning disability and anomalies).
• Robertsonian translocation - two acrocentric chromosomes (13, 14, 15, 21, 22) fuse at the centromere - a carrier has 45 chromosomes.
  • Translocation Down syndrome - about 4% of Down syndrome, often from a parent carrying a balanced 14;21 Robertsonian translocation.
  • Recurrence risk is much higher than for non-disjunction - about 10–15% if the mother is the carrier, about 1% if the father; 100% for a 21;21 translocation carrier.
• Inversions - a segment reversed; carriers are usually healthy but may have unbalanced offspring.
• When to karyotype parents - a child with translocation Down syndrome or an unbalanced rearrangement; recurrent miscarriage with an unbalanced rearrangement in pregnancy tissue; infertility.
• Cancer translocations (somatic) - e.g. t(9;22) Philadelphia chromosome (BCR–ABL1) in CML; t(15;17) in acute promyelocytic leukaemia; t(8;14) in Burkitt lymphoma.

Down Syndrome (Trisomy 21)

• The commonest chromosomal cause of learning disability - about 1 in 1,000 live births in the UK (higher without antenatal screening and termination; rising maternal age increases risk).
• Causes - non-disjunction about 95% (maternal age-related; low recurrence - about 1% or age-related risk); Robertsonian translocation about 4% (karyotype parents); mosaicism about 1–2%.
• Features at birth - hypotonia, upslanting palpebral fissures, epicanthic folds, flat facial profile, small ears, protruding tongue, Brushfield spots on the iris, single palmar crease, sandal gap between the first and second toes, short stature, excess nuchal skin.
• Congenital anomalies:
  • Congenital heart disease in about 40–50% - atrioventricular septal defect (most characteristic), VSD, ASD, PDA, tetralogy of Fallot - echocardiogram for all newborns.
  • GI - duodenal atresia ("double bubble" on X-ray), Hirschsprung disease, anorectal malformations, coeliac disease (later).
• Childhood problems - learning disability (variable, usually mild to moderate), hearing loss (glue ear), visual problems (cataracts, refractive errors, keratoconus), hypothyroidism (congenital and acquired), leukaemia (transient abnormal myelopoiesis in newborns; ALL and AML risk), obstructive sleep apnoea, atlantoaxial instability, epilepsy (infantile spasms), autism.
• Surveillance - growth on Down syndrome-specific charts, regular thyroid function tests, hearing and vision checks, cardiac follow-up, sleep studies if symptoms, annual health check from age 14 (learning disability register).
• Life expectancy now around 60 years in the UK.

Down Syndrome - Adult Health

• Alzheimer's disease - very high risk (extra copy of the APP gene on chromosome 21) - most develop amyloid plaques by 40; dementia often from the late 40s or 50s.
  • Early signs - change in personality or behaviour, loss of skills, new-onset seizures in an adult.
  • Baseline cognitive and functional assessment around age 30; screen for reversible causes (hypothyroidism, hearing and vision loss, depression, sleep apnoea, B12).
• Thyroid disease - hypothyroidism common; also hyperthyroidism.
• Cardiac - acquired valve disease (mitral valve prolapse, aortic regurgitation) in adults even without congenital disease; Eisenmenger syndrome after unrepaired defects.
• Musculoskeletal - atlantoaxial instability (neck pain, gait change, weakness, incontinence - urgent assessment; care with neck positioning during anaesthesia), early osteoarthritis, osteoporosis.
• Other - obesity, obstructive sleep apnoea, coeliac disease, diabetes (type 1), skin problems, early menopause, depression, cataracts and keratoconus, hearing loss.
• Cancer - lower risk of most solid tumours; higher risk of leukaemia (in childhood) and testicular cancer.
• Reasonable adjustments - Mental Capacity Act assessments, easy-read information, carers' involvement, avoid diagnostic overshadowing (attributing new symptoms to the learning disability).
• LeDeR (Learning from Lives and Deaths) reviews highlight avoidable deaths in people with learning disabilities - commonly from respiratory infection, aspiration and delayed diagnosis.

💡 Clinical Pearl: New seizures, loss of skills or a change in behaviour in an adult with Down syndrome - think early Alzheimer's disease, but first exclude hypothyroidism, hearing or vision loss, depression, sleep apnoea and pain.

Edwards (Trisomy 18) and Patau (Trisomy 13) Syndromes

• Edwards syndrome (trisomy 18) - about 1 in 5,000–6,000 births; most die before birth.
  • Features - intrauterine growth restriction, small mouth and jaw (micrognathia), prominent occiput, low-set ears, clenched hands with overlapping fingers (index over middle, little over ring), rocker-bottom feet, short sternum.
  • Anomalies - heart defects (VSD, ASD, PDA - in most), exomphalos, diaphragmatic hernia, oesophageal atresia, renal anomalies, severe learning disability.
  • Prognosis - most babies born alive die within the first weeks or months; around 10% survive the first year.
• Patau syndrome (trisomy 13) - about 1 in 10,000 births.
  • Features - holoprosencephaly (failure of forebrain division), cleft lip and palate, microphthalmia or anophthalmia, polydactyly (postaxial), scalp defects (cutis aplasia), microcephaly, rocker-bottom feet.
  • Anomalies - heart defects, polycystic kidneys, exomphalos, severe learning disability.
  • Prognosis - very poor; most die within the first weeks; some survive longer.
• Antenatal screening - combined test (low hCG and low PAPP-A in both), NIPT, anomaly scan; diagnosis by CVS or amniocentesis (QF-PCR).
• Care - individualised, family-centred decisions with neonatology and palliative care; parallel planning; growing recognition that some families choose active treatment.

Turner Syndrome (45,X)

• Females with a missing or abnormal second X chromosome - about 1 in 2,000–2,500 live-born girls; very common in miscarriage. Karyotype - 45,X (about half), mosaicism (45,X/46,XX), isochromosome Xq, ring X; Y chromosome material in some (risk of gonadoblastoma - prophylactic gonadectomy).
• No association with maternal age; learning is usually normal (some specific difficulties with visuospatial skills and maths).
• Features:
  • Newborn - lymphoedema of hands and feet, webbed neck, cystic hygroma or raised nuchal translucency antenatally.
  • Childhood - short stature (the commonest feature), broad "shield" chest with widely spaced nipples, low hairline, cubitus valgus, short fourth metacarpals, multiple pigmented naevi, nail dysplasia.
  • Puberty - primary ovarian insufficiency (streak ovaries) - absent or arrested puberty, primary amenorrhoea, infertility (raised FSH and LH).
• Associated conditions:
  • Cardiac - bicuspid aortic valve (about 30%), coarctation of the aorta, aortic dilatation and aortic dissection (higher risk - especially in pregnancy), hypertension - lifelong cardiac imaging (echo and MRI).
  • Renal - horseshoe kidney and other anomalies.
  • Other - hypothyroidism (autoimmune), coeliac disease, diabetes, raised liver enzymes, hearing loss, osteoporosis.
• Treatment - growth hormone (improves final height); oestrogen replacement to induce puberty and continue to the age of natural menopause (bone and heart health); fertility - egg donation (pregnancy is high-risk - cardiology review first).

Klinefelter Syndrome (47,XXY)

• The commonest sex chromosome disorder in males - about 1 in 600 males; most are never diagnosed.
• Associated with maternal age (and paternal non-disjunction in about half).
• Features:
  • Tall stature with long legs, small firm testes, gynaecomastia, reduced body and facial hair, female fat distribution.
  • Hypergonadotropic hypogonadism - low testosterone, raised LH and FSH; incomplete puberty.
  • Infertility - azoospermia in most (the common presentation in adulthood).
  • Learning - normal intelligence usually, but speech, language and reading difficulties are common; behavioural and social difficulties.
• Associated risks - osteoporosis, type 2 diabetes and metabolic syndrome, VTE, autoimmune disease (SLE), male breast cancer (increased risk), mediastinal germ cell tumours, depression.
• Diagnosis - karyotype (variants - 48,XXXY, 49,XXXXY are more severe; mosaics milder).
• Treatment - testosterone replacement (from puberty - improves bone density, muscle, energy, sexual function; doesn't restore fertility); micro-TESE (testicular sperm extraction) with ICSI can allow biological fatherhood - consider before starting testosterone; mastectomy for gynaecomastia if wanted; educational support.

Other Sex Chromosome Variations and DSD

• Triple X syndrome (47,XXX) - about 1 in 1,000 females; tall; usually healthy; some learning and speech delays, emotional difficulties, early ovarian insufficiency; most undiagnosed.
• 47,XYY - about 1 in 1,000 males; tall; usually normal fertility; increased risk of speech delay, learning and attention difficulties, autism; mostly undiagnosed.
• Differences (disorders) of sex development (DSD) - congenital conditions where chromosomal, gonadal or anatomical sex is atypical:
  • 46,XX DSD - commonest is congenital adrenal hyperplasia (21-hydroxylase deficiency - autosomal recessive) - virilised genitalia in girls; salt-wasting crisis in the first 2 weeks (hyponatraemia, hyperkalaemia, shock - boys may present only with this); raised 17-hydroxyprogesterone; hydrocortisone and fludrocortisone.
  • 46,XY DSD - androgen insensitivity syndrome (X-linked AR gene - complete form: female appearance, primary amenorrhoea, absent uterus, inguinal testes), 5-alpha-reductase deficiency, gonadal dysgenesis.
  • Sex chromosome DSD - Turner, Klinefelter, 45,X/46,XY mosaicism.
• Newborn with atypical genitalia - urgent specialist (multidisciplinary DSD team) assessment; avoid assigning sex until assessed; check electrolytes and glucose (CAH); karyotype or QF-PCR for sex chromosomes; sensitive communication with parents.

22q11.2 Deletion Syndrome

• The commonest microdeletion syndrome - about 1 in 3,000–6,000 births; previously called DiGeorge or velocardiofacial syndrome; usually de novo (about 10% inherited - autosomal dominant, 50% risk to children).
• Features (very variable):
  • Cardiac - conotruncal defects - tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, VSD.
  • Palate - cleft palate, velopharyngeal insufficiency (nasal speech, feeding difficulties).
  • Immune - thymic hypoplasia - T-cell deficiency (usually mild; rarely severe - use irradiated blood products until immune function known; avoid live vaccines if severe).
  • Endocrine - hypocalcaemia from hypoparathyroidism (neonatal seizures; can recur in adolescence, illness or surgery), hypothyroidism.
  • Face - subtle - hooded eyelids, small ears, prominent nasal bridge, small mouth.
  • Learning and mental health - learning difficulties, ADHD, autism, anxiety; about 25% develop schizophrenia or psychosis in adolescence or adulthood.
  • Other - renal anomalies, scoliosis, autoimmune disease (cytopenias, arthritis), early-onset Parkinson's disease.
• Diagnosis - microarray (or FISH).
• Management - multidisciplinary; calcium and thyroid monitoring; immunology review; cardiac and palate surgery; mental health surveillance into adulthood; test parents.

Williams Syndrome

• 7q11.23 microdeletion including the elastin (ELN) gene - about 1 in 7,500–10,000 births; usually de novo (autosomal dominant if passed on).
• Features:
  • Face - "elfin" features - broad forehead, periorbital fullness, stellate (star-like) iris pattern, short upturned nose, long philtrum, wide mouth with full lips.
  • Cardiovascular - supravalvular aortic stenosis (most characteristic), peripheral pulmonary artery stenosis, renal artery stenosis, hypertension.
  • Hypercalcaemia in infancy (irritability, poor feeding, constipation) - avoid vitamin D supplements unless needed.
  • Learning and behaviour - mild to moderate learning disability with relative strength in language; very sociable, friendly, "cocktail party" personality; anxiety and phobias; ADHD; hyperacusis; love of music.
  • Other - short stature, joint laxity then contractures, hoarse voice, dental anomalies, diabetes in adults, hypothyroidism.
• Diagnosis - microarray or FISH.
• Surveillance - cardiology (echo), BP in all limbs, calcium, thyroid, renal ultrasound, glucose in adults; anaesthetic risk (coronary artery involvement - sudden death under anaesthesia reported).

Other Microdeletion Syndromes

Prader–Willi Syndrome

• Loss of the paternally expressed genes at 15q11–q13 - paternal deletion (about 70%), maternal uniparental disomy (about 25%), imprinting defect (rare); about 1 in 15,000–25,000 births.
• Features:
  • Infancy - severe hypotonia ("floppy baby"), poor suck and feeding difficulties (may need tube feeding), weak cry, undescended testes.
  • Childhood onwards - hyperphagia (insatiable appetite from age 2–8), food-seeking behaviour, obesity (if food not controlled), short stature, small hands and feet, almond-shaped eyes, hypogonadism.
  • Learning and behaviour - mild to moderate learning disability, temper tantrums, obsessive-compulsive behaviour, skin picking, psychosis risk (especially with maternal UPD).
  • Other - high pain threshold, reduced vomiting (gastric rupture risk after binge eating), temperature instability, sleep apnoea, scoliosis, type 2 diabetes, osteoporosis.
• Diagnosis - DNA methylation test at 15q11–q13 (detects all mechanisms); microarray to identify a deletion.
• Management - feeding support in infancy; strict food environment (locked kitchens); growth hormone (improves body composition, height, muscle tone - sleep study before); sex hormones; behavioural support; obesity complications.
• Recurrence risk - low (under 1%) for deletion or UPD; up to 50% with an imprinting centre defect.

Angelman Syndrome

• Loss of the maternally expressed UBE3A gene at 15q11–q13 - maternal deletion (about 70%), paternal UPD, imprinting defect, or UBE3A variant; about 1 in 12,000–20,000.
• Features:
  • Severe learning disability with absent or minimal speech (understanding better than expression).
  • Ataxic, jerky gait ("puppet-like"), tremor, arms raised when walking.
  • Happy demeanour - frequent laughing and smiling, easily excited, hand-flapping.
  • Seizures (most - onset under 3 years) with a characteristic EEG; microcephaly.
  • Sleep problems, fascination with water, fair skin and hair (deletion type), wide mouth, scoliosis.
• Diagnosis - methylation test at 15q11–q13 (detects deletion, UPD and imprinting defects); UBE3A sequencing if methylation is normal.
• Management - antiseizure medicines, communication aids, sleep management, physiotherapy; normal life expectancy in most.
• Recurrence risk - low for deletion or UPD; up to 50% if a UBE3A variant or imprinting centre defect is inherited from the mother.

Beckwith–Wiedemann and Silver–Russell Syndromes

• Beckwith–Wiedemann syndrome (11p15 imprinting) - about 1 in 10,000; more common after assisted reproduction.
  • Features - overgrowth (large for gestational age), macroglossia (feeding, airway and speech problems), exomphalos or umbilical hernia, lateralised overgrowth (hemihypertrophy), ear creases and pits, organomegaly.
  • Neonatal hypoglycaemia (hyperinsulinism) - monitor glucose.
  • Embryonal tumours - Wilms' tumour, hepatoblastoma - abdominal ultrasound every 3 months until age 7 (and AFP for hepatoblastoma in some protocols) depending on molecular subtype.
• Silver–Russell syndrome (11p15 hypomethylation or maternal UPD7):
  • Intrauterine and postnatal growth restriction with relative macrocephaly (head size preserved), triangular face, prominent forehead, body asymmetry, feeding difficulties, hypoglycaemia, fifth finger clinodactyly.
  • Management - nutritional support, prevent hypoglycaemia, growth hormone.
• Both diagnosed by methylation testing at 11p15 (and UPD studies).

Chromosomal Disorders at a Glance

Spot the Diagnosis

Exam-style Scenarios

1. A newborn has hypotonia, upslanting palpebral fissures and a single palmar crease. Parents are 28 and 30.
Answer: Suspected Down syndrome.

• Urgent QF-PCR for rapid confirmation, then karyotype to look for a translocation (which would mean parental karyotypes are needed).
• Echocardiogram (AVSD), check for duodenal atresia and Hirschsprung disease, full blood count (transient abnormal myelopoiesis), thyroid function, hearing and eye checks.
• Sensitive disclosure to both parents together; support organisations; recurrence about 1% if non-disjunction.

2. A 15-year-old girl has not started her periods. She is on the 0.4th centile for height. FSH and LH are raised.
Answer: Turner syndrome likely (primary ovarian insufficiency).

• Karyotype - look for Y material (gonadectomy if present).
• Echocardiogram or cardiac MRI (bicuspid aortic valve, coarctation, aortic dilatation), renal ultrasound, thyroid function, coeliac serology, hearing.
• Oestrogen replacement to induce puberty; growth hormone (limited benefit at this age); fertility counselling (egg donation).

3. A 32-year-old man attends a fertility clinic. He is tall with small firm testes and mild gynaecomastia. Semen analysis shows azoospermia. LH and FSH are high and testosterone low.
Answer: Klinefelter syndrome (47,XXY).

• Confirm with a karyotype.
• Discuss micro-TESE with ICSI before starting testosterone (testosterone suppresses sperm production).
• Testosterone replacement; bone density; screen for diabetes and metabolic risk; awareness of breast cancer risk.

4. A 2-day-old baby with tetralogy of Fallot has a seizure. Calcium is 1.6 mmol/L.
Answer: 22q11.2 deletion syndrome with hypoparathyroidism.

• IV calcium gluconate; check magnesium and PTH; microarray or FISH.
• Use irradiated blood products until T-cell function is known; immunology review; delay live vaccines.
• Test parents (autosomal dominant); long-term follow-up for palate, learning and mental health problems.

5. A 3-year-old boy is obese and constantly seeking food. He was a floppy baby who needed tube feeding. He has small hands and undescended testes.
Answer: Prader–Willi syndrome.

• Methylation test at 15q11–q13; microarray to look for a deletion.
• Strict dietary environment, dietitian, growth hormone (after sleep study), orchidopexy, behavioural support.
• Recurrence usually low (deletion or maternal UPD) - clinical genetics counselling.

Key Points

• Non-disjunction (maternal age) causes most trisomies; recurrence risk is low unless a parent carries a translocation.
• Down syndrome - AVSD, duodenal atresia, hypothyroidism, leukaemia, hearing and vision problems, early Alzheimer's, atlantoaxial instability.
• Edwards - overlapping fingers, rocker-bottom feet; Patau - holoprosencephaly, cleft lip, polydactyly.
• Turner - short stature, coarctation, bicuspid aortic valve, horseshoe kidney, ovarian insufficiency; GH and oestrogen.
• Klinefelter - tall, small testes, high LH and FSH, infertility; micro-TESE before testosterone.
• 22q11.2 deletion - conotruncal heart defects, cleft palate, hypocalcaemia, T-cell deficiency, psychosis.
• Williams - supravalvular aortic stenosis, hypercalcaemia, sociable personality.
• Prader–Willi (paternal loss) - neonatal hypotonia then hyperphagia; Angelman (maternal loss) - absent speech, ataxia, seizures, happy.
• Beckwith–Wiedemann - overgrowth, macroglossia, exomphalos, Wilms' surveillance.
• CAH - salt-wasting crisis in the first 2 weeks; urgent assessment of atypical genitalia.

Guidelines and Further Reading

• Down Syndrome Medical Interest Group (DSMIG UK): Health surveillance guidelines for children and adults with Down syndrome
• International Turner Syndrome Consensus Group: Clinical practice guidelines for the care of girls and women with Turner syndrome (2024)
• European Academy of Andrology: Guidelines on Klinefelter syndrome
• International consensus statements on 22q11.2 deletion syndrome; Williams syndrome; Beckwith–Wiedemann syndrome
• NHS England: LeDeR - Learning from Lives and Deaths of people with a learning disability and autistic people
• Unique - Rare Chromosome Disorder Support Group (family information)
• BNF - for current doses