Clinical Genetics: DNA, Genes and Chromosomes

• Foundations: DNA, Genes and Chromosomes | Types of Genetic Variant | Key Terms -Penetrance, Expressivity, Mosaicism
• Inheritance: Autosomal Dominant Inheritance | Autosomal Recessive Inheritance | X-linked Inheritance | Mitochondrial Inheritance | Imprinting, Anticipation and Uniparental Disomy | Multifactorial and Polygenic Disease
• In practice: Drawing and Reading a Pedigree | Calculating Genetic Risk | Taking a Genetic Family History | Dysmorphology and Recognising a Syndrome
• Revision: Inheritance Patterns at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧬 Genetic basics, inheritance and pedigrees -page 1 of the Clinical Genetics chapter. Genetics is no longer a niche specialty: genomic tests are now ordered by mainstream clinicians across the NHS, and every doctor needs to recognise inheritance patterns, take a three-generation family history and know when to refer. This page covers the building blocks -how variants cause disease, how they are passed on, and how to work out who is at risk.
Your four questions for every possible genetic condition: Could this be genetic (family history, early onset, multiple or rare features)? What is the likely inheritance pattern? Who else in the family is at risk? Will a diagnosis change management for the patient or relatives?

DNA, Genes and Chromosomes

• The human genome -about 3 billion base pairs; about 20,000 protein-coding genes, which make up only around 1–2% of the genome; the rest includes regulatory regions, non-coding RNA genes and repetitive DNA.
• Chromosomes -46 in 23 pairs: 22 pairs of autosomes plus the sex chromosomes (XX female, XY male). Each chromosome has a short arm (p) and a long arm (q) joined at the centromere -e.g. 22q11.2 is a band on the long arm of chromosome 22.
• Genes -exons (coding) and introns (removed by splicing); promoters and enhancers control expression.
• From gene to protein -DNA → transcription → messenger RNA → splicing → translation (triplet codons) → protein.
• Mitochondrial DNA -a small circular genome (37 genes) inherited from the mother; many copies per cell.
• Germline vs somatic:
  • Germline variants -present from conception in every cell (including eggs or sperm) -can be inherited and passed on.
  • Somatic variants -acquired in one tissue during life (e.g. in a tumour) -not passed on to children.
• Genotype and phenotype -genotype is the genetic make-up; phenotype is the observable features.
• Alleles -versions of a gene; homozygous (two identical alleles), heterozygous (two different), compound heterozygous (two different disease-causing variants in the same gene), hemizygous (one copy only -X-linked genes in males).

Types of Genetic Variant

• "Variant" is now preferred to "mutation" -most variants are harmless; only some are disease-causing (pathogenic).
• Single nucleotide variants:
  • Missense -one amino acid changed (e.g. HbS in sickle cell disease -glutamic acid to valine).
  • Nonsense -creates a premature stop codon -usually loss of function.
  • Synonymous -no amino acid change (usually harmless, though some affect splicing).
  • Splice-site -disrupts splicing.
• Insertions and deletions -frameshift if not a multiple of 3 bases (usually severe -e.g. Duchenne muscular dystrophy), in-frame if a multiple of 3 (often milder -e.g. Becker muscular dystrophy; F508del in cystic fibrosis is an in-frame deletion of one amino acid).
• Copy number variants -deletions or duplications of larger segments (e.g. 22q11.2 deletion), detected by microarray.
• Repeat expansions -unstable triplet or other repeats that grow between generations (Huntington's disease, myotonic dystrophy, fragile X syndrome, Friedreich's ataxia).
• Chromosomal abnormalities -aneuploidy (an extra or missing chromosome -trisomy 21), translocations, inversions, large deletions.
• Mechanisms:
  • Loss of function -reduced or absent protein (most recessive conditions; haploinsufficiency in some dominant conditions).
  • Gain of function -new or increased activity (e.g. achondroplasia -FGFR3).
  • Dominant negative -abnormal protein disrupts the normal one (e.g. collagen in osteogenesis imperfecta, fibrillin-1 in Marfan syndrome).

Key Terms -Penetrance, Expressivity, Mosaicism

• Penetrance -the proportion of people with a pathogenic variant who develop the condition at all.
  • Complete -Huntington's disease (40 or more CAG repeats) is almost fully penetrant by old age.
  • Incomplete (reduced) -BRCA1 (lifetime breast cancer risk about 60–70%, not 100%), hereditary haemochromatosis (many C282Y homozygotes never develop iron overload).
  • Age-dependent -penetrance rises with age (Huntington's, familial cancers).
• Variable expressivity -people with the same variant are affected to different degrees (e.g. neurofibromatosis type 1 -a few café-au-lait patches in a parent, severe plexiform neurofibromas in a child).
• Pleiotropy -one gene affects several organ systems (Marfan -eyes, skeleton, aorta).
• Locus heterogeneity -the same condition caused by variants in different genes (e.g. retinitis pigmentosa, hypertrophic cardiomyopathy, Lynch syndrome).
• De novo variant -new in the child, not present in either parent (e.g. most cases of achondroplasia; many neurodevelopmental disorders).
• Mosaicism:
  • Somatic mosaicism -a variant in some body cells only (e.g. segmental NF1; mosaic Down syndrome -milder).
  • Gonadal (germline) mosaicism -a variant in some eggs or sperm -healthy parents with no detectable variant can have more than one affected child (recurrence risk after an apparently de novo dominant condition is about 1–2%, not zero).
• Founder effect -high frequency in a population descended from a small group (e.g. BRCA founder variants in Ashkenazi Jewish people; Tay–Sachs disease).
• Heterozygote advantage -carriers protected (sickle cell trait and malaria).

💡 Clinical Pearl: A negative family history doesn't exclude a genetic condition -think de novo variants, reduced penetrance, non-paternity, adoption, small families, early deaths from other causes, and recessive inheritance (where parents are usually unaffected carriers).

Autosomal Dominant Inheritance

• One copy of the variant is enough to cause the condition.
• Pedigree features -affected people in every generation ("vertical" pattern); males and females equally affected; male-to-male transmission occurs (rules out X-linked); an affected person's child has a 50% (1 in 2) risk.
• Modifiers -reduced penetrance (apparent "skipped" generations), variable expressivity, de novo variants, anticipation in repeat expansions.
• Examples:
  • Huntington's disease, myotonic dystrophy, spinocerebellar ataxias.
  • Familial hypercholesterolaemia, hypertrophic cardiomyopathy, long QT syndrome, Marfan syndrome, vascular Ehlers–Danlos syndrome.
  • Hereditary cancer syndromes -BRCA1 and BRCA2, Lynch syndrome, familial adenomatous polyposis, Li–Fraumeni syndrome, MEN1 and MEN2, von Hippel–Lindau.
  • Neurofibromatosis types 1 and 2, tuberous sclerosis complex.
  • Adult polycystic kidney disease (PKD1, PKD2), hereditary haemorrhagic telangiectasia, achondroplasia, osteogenesis imperfecta (most), hereditary spherocytosis (most), acute intermittent porphyria.
• Mnemonic -dominant conditions often affect structural proteins and receptors; recessive conditions often affect enzymes (with exceptions).

Autosomal Recessive Inheritance

• Two copies (one from each parent) are needed -homozygous or compound heterozygous; carriers (one copy) are usually healthy.
• Pedigree features -usually one generation affected (siblings -"horizontal" pattern); parents are unaffected carriers; males and females equally affected; more common with consanguinity (parents related -e.g. first cousins share about 1/8 of their genes).
• Risks for two carrier parents -each child: 25% affected, 50% carrier, 25% unaffected non-carrier. An unaffected sibling of an affected child has a 2/3 chance of being a carrier.
• Examples:
  • Cystic fibrosis (CFTR) -carrier frequency about 1 in 25 in white Northern Europeans.
  • Sickle cell disease and beta-thalassaemia.
  • Hereditary haemochromatosis (HFE C282Y).
  • Spinal muscular atrophy, Friedreich's ataxia.
  • Inborn errors of metabolism -phenylketonuria, MCADD, homocystinuria, Tay–Sachs disease, Gaucher disease, glycogen storage diseases, mucopolysaccharidoses (except Hunter -X-linked).
  • Wilson's disease, alpha-1 antitrypsin deficiency (co-dominant), congenital adrenal hyperplasia (21-hydroxylase), primary ciliary dyskinesia, autosomal recessive polycystic kidney disease, oculocutaneous albinism.

X-linked Inheritance

• X-linked recessive:
  • Mainly males affected (one X -hemizygous); females are usually carriers (sometimes mildly affected through skewed X-inactivation).
  • No male-to-male transmission.
  • Carrier mother -each son has a 50% chance of being affected; each daughter 50% chance of being a carrier.
  • Affected father -all daughters are carriers ("obligate carriers"); no sons affected.
  • Affected males related through females (maternal uncles, cousins via sisters) -"knight's move" pattern.
  • Examples -Duchenne and Becker muscular dystrophy, haemophilia A and B, G6PD deficiency, red–green colour blindness, Fabry disease, Hunter syndrome, X-linked agammaglobulinaemia (Bruton's), Wiskott–Aldrich syndrome, Lesch–Nyhan syndrome, nephrogenic diabetes insipidus (AVPR2), Kennedy disease (X-linked spinobulbar muscular atrophy), X-linked ichthyosis.
• X-linked dominant:
  • Both sexes affected; females often more mildly (two X chromosomes); affected father passes it to all daughters and no sons.
  • Some are lethal in males -seen almost only in females (e.g. Rett syndrome -MECP2, incontinentia pigmenti).
  • Examples -X-linked hypophosphataemic rickets, Alport syndrome (X-linked form -most cases), fragile X syndrome (often described as X-linked with variable expression in females).
• X-inactivation (lyonisation) -one X is randomly switched off in each female cell; skewed inactivation explains symptomatic female carriers (e.g. manifesting DMD carriers -cardiomyopathy).
• Y-linked -rare (some male infertility genes); father to all sons.

Mitochondrial Inheritance

• Mitochondrial DNA is inherited from the mother only -an affected mother can pass it to all her children; an affected father does not pass it on.
• Heteroplasmy -cells contain a mixture of normal and variant mitochondrial DNA; the proportion varies between tissues and between children (hard to predict risk).
• Threshold effect -disease appears once the variant proportion is high enough; high-energy tissues are most affected (brain, muscle, heart, eye, ear, pancreas, kidney).
• Many "mitochondrial diseases" are actually caused by nuclear genes (autosomal recessive or dominant inheritance -e.g. POLG).
• Examples:
  • MELAS -mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (m.3243A>G -also causes maternally inherited diabetes and deafness).
  • MERRF -myoclonic epilepsy with ragged red fibres.
  • Leber hereditary optic neuropathy -painless sequential visual loss in young men.
  • Kearns–Sayre syndrome (usually a sporadic deletion) -ophthalmoplegia, ptosis, retinopathy, heart block.
  • Aminoglycoside-induced deafness -m.1555A>G (MT-RNR1) -see page 6.
• Clues -multisystem disease, raised lactate, ragged red fibres on muscle biopsy, maternal family history, ptosis and ophthalmoplegia, deafness with diabetes.
• Mitochondrial donation -legal in the UK since 2015 (HFEA-licensed, Newcastle) to prevent transmission of serious mitochondrial DNA disease.

Imprinting, Anticipation and Uniparental Disomy

• Genomic imprinting -some genes are expressed only from the mother's or only from the father's copy (the other is silenced by methylation).
  • Prader–Willi syndrome -loss of the paternal 15q11–q13 region (paternal deletion or maternal uniparental disomy) -neonatal hypotonia and poor feeding, then hyperphagia and obesity, learning disability, hypogonadism, short stature.
  • Angelman syndrome -loss of the maternal copy (UBE3A) -severe learning disability, absent speech, ataxia, seizures, happy demeanour with frequent laughter, microcephaly.
  • Beckwith–Wiedemann syndrome (11p15) -overgrowth, macroglossia, exomphalos, hemihypertrophy, neonatal hypoglycaemia, Wilms' tumour risk (abdominal ultrasound surveillance).
  • Silver–Russell syndrome -growth restriction, relative macrocephaly, triangular face, body asymmetry.
• Uniparental disomy -both copies of a chromosome from one parent (causes imprinting disorders, or unmasks a recessive condition from a single carrier parent).
• Anticipation -a repeat expansion condition becomes more severe or earlier in onset with each generation as the repeat grows:
  • Huntington's disease -larger expansions through the father (juvenile HD usually paternally inherited).
  • Myotonic dystrophy type 1 -large expansions through the mother (congenital myotonic dystrophy).
  • Fragile X -premutation expands to full mutation through the mother.

Multifactorial and Polygenic Disease

• Most common diseases are multifactorial -many genetic variants of small effect plus environment: type 2 diabetes, coronary heart disease, hypertension, asthma, schizophrenia, autism, inflammatory bowel disease, most cancers, neural tube defects, cleft lip and palate, congenital heart disease, pyloric stenosis, developmental dysplasia of the hip, club foot.
• Features -family clustering without a Mendelian pattern; risk to relatives higher with closer relationship, more affected relatives, more severe disease, and when the affected person is of the less commonly affected sex (e.g. pyloric stenosis in a girl).
• Recurrence risks -usually low (typically 2–5% for first-degree relatives) -counselling uses empirical data.
• Neural tube defects -folic acid 400 micrograms daily before conception and for 12 weeks; 5 mg daily if higher risk (previous NTD, family history, antiepileptic drugs, diabetes, BMI 30 or more, sickle cell disease, coeliac disease -check current NICE and RCOG advice).
• Polygenic risk scores -combine many small-effect variants to estimate risk (e.g. coronary heart disease, breast cancer) -under research; not yet routine NHS practice.
• HLA associations -HLA-B27 (ankylosing spondylitis), HLA-DQ2/DQ8 (coeliac disease -a negative result helps exclude it), HLA-DR4 (rheumatoid arthritis), HLA-DR3 (type 1 diabetes, Graves' disease, SLE).

Drawing and Reading a Pedigree

• Standard symbols:
  • Square -male; circle -female; diamond -sex unknown or not stated.
  • Filled shape -affected; half-filled or dot in the centre -carrier (dot in a circle usually means X-linked carrier).
  • Diagonal line through the shape -deceased (record age and cause of death).
  • Horizontal line between partners; double line -consanguineous relationship.
  • Vertical line down to a horizontal sibship line; siblings in birth order left to right.
  • Arrow -the proband (the person who brought the family to attention); the consultand is the person seeking advice.
  • Small triangle -miscarriage; P in a shape -pregnancy; twins drawn from one point (monozygotic joined by a bar).
  • Generations numbered with Roman numerals (I, II, III); individuals with Arabic numerals.
• Reading a pedigree:
  1. Are both sexes affected equally? (If mostly males -think X-linked recessive.)
  2. Is every generation affected? (Yes -dominant; skipped -recessive or reduced penetrance.)
  3. Is there male-to-male transmission? (Excludes X-linked.)
  4. Do affected fathers have all daughters affected and no sons? (X-linked dominant.)
  5. Is it passed only through mothers? (Mitochondrial.)
  6. Is there consanguinity and affected siblings with unaffected parents? (Autosomal recessive.)

Calculating Genetic Risk

Taking a Genetic Family History

• Three generations -the patient's children, siblings, parents, aunts and uncles, grandparents, and cousins where relevant.
• For each relative -current age or age at death, cause of death, conditions and age at diagnosis (early onset is a key clue), which side of the family.
• Ask specifically about:
  • Cancers (type and age), heart disease and sudden death under 40, high cholesterol, stroke at a young age.
  • Learning disability, developmental delay, epilepsy, deafness, blindness.
  • Miscarriages, stillbirths, infant deaths, infertility.
  • Consanguinity (asked sensitively), ancestry or ethnicity (some conditions are more common in certain populations).
  • Known genetic diagnoses or previous genetic tests in the family.
• Be sensitive -adoption, donor conception, non-paternity and family estrangement are common; confirm diagnoses (records, death certificates) where possible.
• Red flags suggesting a genetic cause:
  • Multiple relatives with the same or related conditions.
  • Early onset of a common condition (e.g. breast cancer under 40, colorectal cancer under 50, MI under 50 in men).
  • Multiple primary cancers or bilateral cancers in one person.
  • Unusual or rare cancers (male breast cancer, medullary thyroid cancer, phaeochromocytoma).
  • Unexplained sudden death in a young person.
  • Two or more congenital anomalies, developmental delay with dysmorphic features.

Dysmorphology and Recognising a Syndrome

• Dysmorphology -the study of unusual physical features that may point to a genetic diagnosis.
• Types of anomaly:
  • Malformation -abnormal development of tissue (e.g. cleft lip, heart defect).
  • Deformation -mechanical forces on normal tissue (e.g. club foot from oligohydramnios).
  • Disruption -destruction of normal tissue (e.g. amniotic bands).
  • Sequence -one anomaly causing a cascade (e.g. Pierre Robin sequence -small jaw → tongue displacement → cleft palate; Potter sequence -renal agenesis → oligohydramnios → lung hypoplasia and facial features).
  • Association -anomalies occurring together more often than chance, without a single known cause (e.g. VACTERL -vertebral, anal, cardiac, tracheo-oesophageal, renal, limb).
  • Syndrome -a recognisable pattern of features with a single cause.
• Examination -growth (height, weight, head circumference on centile charts), face (eyes, ears, nose, philtrum, jaw), hands and feet (single palmar crease, clinodactyly, polydactyly), skin (café-au-lait patches, ash leaf macules), heart, genitalia, spine; parents' features for comparison.
• Tools -photographs (with consent), databases (e.g. DECIPHER, Face2Gene), clinical genetics referral.
• Minor anomalies are common in isolation; three or more increase the chance of a major anomaly or syndrome.
• Environmental mimics -fetal alcohol spectrum disorder, fetal valproate syndrome, maternal diabetes, congenital infections (CMV, rubella, toxoplasmosis, Zika).

Inheritance Patterns at a Glance

Spot the Diagnosis

Exam-style Scenarios

1. A couple's first child has cystic fibrosis. Both parents are well. They ask the chance that their next child will be affected, and whether their healthy daughter is a carrier.
Answer: Autosomal recessive -both parents are carriers.

• Each pregnancy: 1 in 4 affected, 1 in 2 carrier, 1 in 4 non-carrier.
• Their healthy daughter has a 2 in 3 chance of being a carrier (she isn't affected, so one of the four outcomes is excluded).
• Offer clinical genetics referral; prenatal diagnosis (CVS) or preimplantation genetic testing are options; cascade carrier testing for relatives.

2. A woman's brother and maternal uncle have Duchenne muscular dystrophy. She is pregnant with a boy.
Answer: X-linked recessive -her mother is an obligate carrier (affected son and affected brother); she has a 1 in 2 prior chance of being a carrier.

• Her son's risk is 1/2 × 1/2 = 1 in 4 before testing.
• Carrier testing (using the family variant) clarifies her risk; urgent clinical genetics referral for prenatal testing options.
• Carriers can have cardiomyopathy -offer cardiac assessment.

3. A 30-year-old man's father has Huntington's disease. He is asymptomatic and asks about testing and his own children's risk.
Answer: Autosomal dominant -his prior risk is 50%; his children's current risk is 25%.

• Predictive testing via clinical genetics with a structured counselling protocol (several appointments, time to reflect, support).
• Discuss implications -no disease-modifying treatment, psychological impact, insurance (see page 6), family planning.
• If he tests positive, each child has a 50% risk; testing of children is usually deferred until they can choose for themselves.

4. A 5-year-old has learning disability and a mother with a premature menopause at 38. Her maternal grandfather has a tremor and ataxia.
Answer: Fragile X syndrome -premutation carriers in the family (FMR1 CGG repeat).

• Mother likely a premutation carrier (fragile X-associated primary ovarian insufficiency); grandfather -FXTAS (fragile X-associated tremor/ataxia syndrome).
• Expansion to a full mutation occurs through the mother (anticipation).
• FMR1 repeat testing; clinical genetics referral; cascade testing for relatives.

5. A child has a dominant condition caused by a de novo variant not found in either parent's blood. The parents want another child.
Answer: Low but real recurrence risk because of possible gonadal mosaicism.

• Quote a recurrence risk of about 1–2% (varies by condition), not zero.
• Prenatal testing for the specific variant can be offered for reassurance.
• The affected child has a 50% risk of passing the condition to their own children.

Key Points

• Germline variants are inherited and present in every cell; somatic variants are acquired (tumours) and not passed on.
• Autosomal dominant -every generation, male-to-male transmission, 50% risk.
• Autosomal recessive -affected siblings, carrier parents, consanguinity, 25% risk; healthy sibling 2/3 carrier.
• X-linked recessive -mostly males, no male-to-male; daughters of affected men are obligate carriers.
• Mitochondrial -passed only by mothers; heteroplasmy causes variable severity.
• Anticipation -Huntington's (paternal), myotonic dystrophy and fragile X (maternal).
• Imprinting -Prader–Willi (paternal loss), Angelman (maternal loss).
• Reduced penetrance and variable expressivity explain "skipped" generations and differing severity.
• A negative family history doesn't exclude genetic disease -de novo variants, recessive inheritance, small families.
• Take a three-generation history with ages at diagnosis; early onset and multiple primaries are red flags.
• Recognise pedigree symbols -square male, circle female, filled affected, arrow proband, double line consanguinity.

Guidelines and Further Reading

• NHS England: Genomic Medicine Service; National Genomic Test Directory
• Health Education England Genomics Education Programme: GeNotes -genomics knowledge hub for clinicians
• Royal College of Physicians / British Society for Genetic Medicine: Consent and confidentiality in genomic medicine
• National Society of Genetic Counselors: Standardized pedigree nomenclature (Bennett et al.)
• Online Mendelian Inheritance in Man (OMIM); DECIPHER database
• BNF -for current doses