2.9.3 Genetic abnormalities, inherited conditions and clinical genetics

Chromosome structure

Acrocentric is told from telocentric by the p arm: acrocentric has a tiny one, telocentric has none.

• A Robertsonian translocation joins the long arms of two acrocentric chromosomes (for example 13 and 14) at the centromere into one metacentric chromosome, and the gene-poor short arms are lost.

• A balanced Robertsonian carrier, such as a 14;21 carrier, is healthy but has a real risk of having a child with translocation Down syndrome.

• Copy number variants are deletions or duplications that change gene dosage, and apparently balanced breakpoints can still disrupt genes.

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Numerical abnormalities and mosaicism

• Aneuploidy is a gain or loss of whole chromosomes, as in the trisomies (trisomy 21 adds a whole chromosome) and the sex chromosome aneuploidies.

• Deletions, single-gene changes and imprinting defects leave the count at 46, so they are not aneuploidy.

• Triploidy is a complete extra haploid set, 69 chromosomes, and is a typical cause of early pregnancy loss.

• Complete autosomal monosomy does not allow survival, but 45,X can.

• Nondisjunction is failed separation of homologues at meiosis I or of sister chromatids at meiosis II.

• Trisomy changes chromosome dosage without necessarily altering the DNA sequence.

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• Mosaicism often gives variable severity, and a blood test can miss mosaicism confined to other tissues.

X-inactivation

• Lyonisation (X-inactivation) silences one X early in development in any cell holding more than one X chromosome, so it shapes the phenotype in conditions with a surplus X, such as XXY.

• The inactive X is condensed in female somatic nuclei as a Barr body.

• Random X-inactivation makes a heterozygous female a functional mosaic, so she is usually less affected than a hemizygous male by an X-linked variant, as in fragile X syndrome.

• Skewed X-inactivation silences the normal X in most cells, so a female carrier of an X-linked variant, including a fragile X full mutation, can express the disorder.

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Mendelian inheritance

• Father-to-son transmission rules out X-linkage, because a father passes his Y to every son and his only X to every daughter.

• Autosomal recessive inheritance seems to skip generations because heterozygous carriers are unaffected, and the trait is absent from earlier generations.

• Consanguinity raises the chance that both parents carry the same rare recessive allele.

• When both parents have the same autosomal recessive condition, both are homozygous, so every child is affected (1 in 1, not 1 in 4).

• The knight's move of X-linked recessive inheritance runs from an affected man through his carrier daughter to an affected grandson; in Duchenne muscular dystrophy it shows as affected brothers, a carrier mother and an affected maternal uncle.

• Enzyme and storage disorders are generally autosomal recessive, but acute intermittent porphyria (HMBS gene, porphobilinogen deaminase) is autosomal dominant.

• Hunter syndrome (mucopolysaccharidosis type II, iduronate sulfatase deficiency) and Lesch-Nyhan syndrome are X-linked recessive, whereas Hurler syndrome (type I) is autosomal recessive.

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Mitochondrial inheritance

• Heteroplasmy means cells carry unequal loads of mutant mitochondrial DNA, and disease appears only above a tissue threshold, so children of one mother differ in severity and some escape disease.

• Leber's hereditary optic neuropathy is a mitochondrial, purely maternally inherited condition.

• MELAS gives stroke-like episodes outside arterial territories, seizures and raised lactate, and is usually caused by m.3243A>G in mitochondrial DNA.

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Penetrance, expressivity and imprinting

• Penetrance is whether a carrier shows the phenotype at all, so an unaffected carrier shows incomplete penetrance.

• Expressivity is how severely or in what form the phenotype shows, so differing severity among affected carriers of one variant is variable expressivity.

• Genomic imprinting makes expression of an allele depend on the sex of the parent it came from, so the same variant causes disease from one parent and stays silent from the other.

• Uniparental disomy gives both copies of a chromosome from one parent, with a normal chromosome count.

Sequence variants and repeat expansion

• Dynamic mutations are unstable trinucleotide repeat expansions that change size between generations.

• Repeat expansion is one mutation class shared by clinically unrelated disorders, such as fragile X syndrome and Huntington's disease.

• Each repeat disorder expands its own repeat unit in its own gene, so the repeat motif identifies the disease.

• Anticipation is progressively earlier onset and greater severity in successive generations, classically from unstable trinucleotide repeat expansion.

• Anticipation differs from variable expressivity, which has no generational trend.

• Repeat disorders differ from contiguous-gene microdeletion syndromes, which are copy number changes without anticipation.

• Myotonic dystrophy type 1 gives grip myotonia, frontal balding, apathy and hypersomnia, and its congenital form follows maternal transmission of a large expansion.

• In Friedreich's ataxia the expansion lowers frataxin production.

• Spinocerebellar ataxia type 3 (Machado-Joseph disease, described in Azorean families) is a CAG expansion in ATXN3 that adds a polyglutamine tract and shows anticipation.

Huntington's disease

• Huntington's disease is an expanded CAG repeat in HTT (huntingtin) at 4p16.3.

• The pathological threshold is about 36 repeats: 36 to 39 show reduced penetrance and 40 or more are fully penetrant.

• The CAG repeat is translated into a long polyglutamine tract, giving huntingtin a toxic gain of function, unlike the gene silencing of fragile X.

• It presents in mid-life with chorea, subcortical cognitive decline and irritability, and mood, behavioural or psychotic symptoms may come before the movement changes.

• Inheritance is autosomal dominant, so the family history is the most important part of the history.

• Anticipation follows meiotic expansion of the unstable repeat, and a longer repeat brings earlier onset.

• The repeat is least stable when a father passes it on, so anticipation and juvenile onset are most marked with paternal transmission, while maternal transmission keeps length fairly stable.

• Juvenile disease often has rigidity and seizures.

Down syndrome

Trisomy 21 is the commonest trisomy compatible with survival to birth, about 1 in 700 births, and its risk rises with maternal age.

• Mosaic Down syndrome is milder in cognition and physique than the other forms, because normal cell lines dilute the dosage effect.

• Parental karyotyping is needed only for the translocation form.

• Signs include intellectual disability, Brushfield spots and a sandal gap.

• Endocardial cushion (atrioventricular septal) defect is the commonest congenital heart lesion.

• APP (amyloid precursor protein), encoded on chromosome 21, is cleaved by beta-secretase then gamma-secretase; trisomy raises its dose by half, so almost everyone with Down syndrome has plaques by 40.

Edwards and Patau syndromes

• Edwards (18) is told from Patau (13) and Down (21) by which chromosome is extra.

• Patau syndrome is more frequent with older mothers.

• A minority of Patau cases arise from a Robertsonian translocation carrying the long arm of a third chromosome 13, so the count stays at 46.

Sex chromosome aneuploidies

• Klinefelter syndrome is primary testicular failure.

• 47,XYY is usually clinically silent, and was historically labelled the "super-male".

• A 1965 secure hospital survey linked XYY with aggression and antisocial behaviour, but the association is modest.

• XYY is told from Klinefelter, XXYY and XX male by its normal testes: those three cause small testes and azoospermia.

• Turner syndrome is the only monosomy compatible with life, and affects only females because no Y directs male development.

• The single X in 45,X is usually maternal, so the lost chromosome is usually paternal.

• The webbed neck comes from fetal lymphatic obstruction.

• Because Turner syndrome is a sporadic error, the recurrence risk in a later pregnancy is not appreciably raised.

Fragile X syndrome

• Fragile X syndrome is the commonest inherited cause of learning disability.

• It is caused by expansion of a CGG repeat in the 5' untranslated region of FMR1 at Xq27.3.

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• The premutation disorders are FXTAS, a late-onset tremor and ataxia chiefly in men, and primary ovarian insufficiency, affecting about 20% of female carriers.

• A premutation expands to a full mutation mainly when a woman passes it on, because instability arises in female meiosis; fathers pass on only premutation-sized alleles.

• Fragile X is conventionally classed as X-linked dominant with reduced penetrance and shows an X-linked pedigree.

• The physical signs are a long narrow face, large protruding ears, joint laxity, tall stature and macroorchidism (large testes after puberty), and they are understated before puberty.

• Behaviour includes gaze aversion, social anxiety, hand flapping, sensory hypersensitivity, autistic features and inattention, with mild intellectual disability.

• Speech is cluttered: fast, uneven in rate and repetitive.

The 15q11-q13 imprinting disorders

Prader-Willi and Angelman syndromes are mirror images at the same imprinted region, and every mechanism below is a parent-of-origin effect.

Prader-Willi syndrome

• It starts with neonatal hypotonia and poor feeding, followed from early childhood by relentless food seeking.

• Hyperphagia and obesity are the defining behavioural feature.

• Other features are intellectual disability, small hands and feet, and compulsive skin picking.

• Short stature comes largely from growth hormone deficiency.

• Hypogonadism gives small or undescended gonads and delayed, incomplete puberty.

Angelman syndrome

• People have a happy, excitable manner with frequent, easily provoked laughter, severe learning disability, absent speech and ataxia.

• Seizures occur in over 80%, usually starting between one and three years, and a distinctive electroencephalogram (EEG) pattern is well established by about two years.

Microdeletion syndromes

• Wolf-Hirschhorn syndrome is a terminal deletion of the short arm of chromosome 4, with its critical region at 4p16.3.

• Hypocalcaemia belongs to 22q11.2 deletion and hypercalcaemia to Williams syndrome.

• 22q11.2 deletion has the strongest psychiatric link with schizophrenia and related psychosis, affecting about one in four adults.

• This is a 25 to 30-fold risk, the largest known single genetic risk, exceeded only by having a monozygotic co-twin with the illness.

• The elastin deletion explains the supravalvular aortic stenosis of Williams syndrome.

• In Williams syndrome, expressive language is relatively good and speech fluent but shallow, while visuospatial skills are markedly weak.

• Indiscriminate hypersociability towards strangers in Williams syndrome sits over impaired social reciprocity.

• SHANK3 is a scaffold protein of the excitatory postsynaptic density.

• Cri du chat is a structural loss of chromosomal material, not a change in chromosome count.

Rett syndrome

• Rett syndrome is caused by mutation of MECP2 (methyl-CpG-binding protein 2) at Xq28, which accounts for nearly all classic cases.

• It is X-linked dominant.

• It is seen almost only in girls because the mutation is usually lethal early in hemizygous boys.

• It almost always arises as a new mutation, mainly in sperm, and a father passes his X only to daughters.

• A girl develops normally at first and then regresses, losing purposeful hand use and speech, with social withdrawal.

• Regression comes with midline hand-wringing stereotypies, gait change, breathing irregularities and slowing head growth.

• Regression also occurs in autism, so regression alone does not separate the two.

Single-gene metabolic and neurological disorders

• Niemann-Pick disease types A and B are caused by acid sphingomyelinase deficiency, so sphingomyelin builds up in lysosomes.

• In Wilson disease, copper in Descemet's membrane forms a Kayser-Fleischer ring.

• Wilson disease gives low caeruloplasmin, low total serum copper and high 24-hour urinary copper.

• Wilson disease is treatable, so it is considered whenever behavioural, liver and movement changes start young.

Neurocutaneous syndromes

• Lisch nodules are small raised tan hamartomas of the iris, seen in most adults with neurofibromatosis type 1.

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Complex inheritance and risk genes

• Single-gene disorders explain a minority of psychiatric presentations, and common psychiatric disorders mainly reflect susceptibility spread across many variants.

• Schizophrenia is complex and polygenic, with heritability about 60 to 80%, more than 100 common risk loci, rarer copy number variants, and familial clustering without a Mendelian pattern.

• Rare large-effect copy number variants, such as 22q11.2 deletion, are enriched in schizophrenia with intellectual deficit.

• Rare copy number variants, including de novo deletions and duplications, are more strongly and consistently associated with autism spectrum disorder than with attention deficit hyperactivity disorder.

• High-risk copy number variants can cross psychotic, developmental and physical phenotypes.

• APP and PSEN2 also cause dominant early-onset Alzheimer's disease, and MAPT and C9orf72 also cause familial frontotemporal dementia.

Genetic testing and prenatal diagnosis

• Screening estimates probability, whereas diagnosis tests for specified abnormalities.

• Combined screening uses nuchal translucency, serum markers and background risk.

• Maternal cell-free DNA mainly samples placental fragments, so a high-chance result needs diagnostic confirmation before any irreversible decision.

• Chorionic villus sampling takes placenta from about 11 weeks, and confined placental mosaicism can complicate it.

• Amniocentesis takes amniotic fluid from about 15 weeks.

• Either procedure adds a miscarriage risk of roughly 0.1 to 0.5%.

• A normal result excludes only the abnormalities the test can detect.

Genetic counselling and DNA banks

• Counselling starts from the person's question, phenotype and pedigree, and explains inheritance, probabilities, mosaicism, penetrance and test limits before testing.

• The counsellor supports informed choice without steering testing or reproductive decisions.

• Predictive testing may come decades before symptoms, so psychological state and suicide risk are assessed.

• Carrier and prenatal testing concern reproductive decisions.

• A variant of uncertain significance cannot by itself establish predictive risk.

• Clinician and patient agree in advance which incidental findings will be returned.

• Positive and negative results can both bring distress, relief, guilt and changed plans.

• Counselling covers what a result means for relatives and encourages disclosure to them while protecting confidentiality.

• Psychiatry assesses capacity, mental state and psychological response, while genetics services bring expertise in inheritance and testing.

• Clinical DNA banks keep samples for later family testing, whereas research biobanks link samples with health data.

• Biobank consent covers access, linkage, commercial use, withdrawal and returned findings.

• De-identification cannot remove the risk that a genome identifies its owner.