Genetic & Congenital Disorders

Genetics is usually learned as a catalogue of syndromes, which is why candidates can recite the features of Down syndrome and still fail a question about recurrence risk.

The organising tool is to classify the error before naming the disease. Is it too much or too little chromosome, a single gene, an imprinted region, or the mitochondrial genome?

Each class behaves differently in three respects that examiners test constantly.

A whole extra chromosome affects hundreds of genes at once, so the phenotype involves many systems, the recurrence risk relates to maternal age, and the test is a karyotype. A single gene defect affects one protein, so the phenotype is narrower, the recurrence risk is a fixed Mendelian fraction, and the test is targeted sequencing.

Imprinted and mitochondrial disorders break Mendelian rules entirely, which is precisely why they are examined out of proportion to their frequency.

1. Aneuploidy and Why Age Matters

Aneuploidy is an abnormal chromosome number, and it usually arises from non-disjunction during meiosis, when a chromosome pair fails to separate.

Most non-disjunction is maternal and occurs in meiosis I, and this explains the maternal age effect that dominates the subject.

The mechanism is worth understanding. A woman's oocytes enter meiosis I before she is born and then arrest, remaining suspended in prophase until that oocyte ovulates decades later. The proteins holding the chromosome pairs together degrade over that time, so the older the oocyte, the more likely the pair separates incorrectly.

Sperm, by contrast, are produced continuously and freshly, which is why paternal age contributes to new dominant point mutations rather than to aneuploidy.

That single difference explains why Down syndrome risk rises with maternal age while achondroplasia and Marfan syndrome from new mutations rise with paternal age.

Aneuploidy is also the commonest cause of miscarriage, so the same mechanism that produces liveborn trisomies produces far more pregnancies that never continue.

2. The Autosomal Trisomies

Three autosomal trisomies are compatible with live birth, and their survival correlates inversely with the size of the chromosome, because larger chromosomes carry more genes and a larger dosage excess.

Down syndrome is the one to know in depth, because its complications determine lifelong management.

Cardiac disease affects around half, with the atrioventricular septal defect being characteristic. Duodenal atresia produces the double bubble sign. Hypothyroidism, atlantoaxial instability, hearing loss, leukaemia and early Alzheimer disease all occur at increased frequency.

Early Alzheimer disease has a direct genetic explanation: the amyloid precursor protein gene lies on chromosome 21, so three copies mean lifelong overproduction of amyloid.

Three cytogenetic mechanisms produce Down syndrome, and the distinction matters entirely for recurrence risk.

Free trisomy 21 from non-disjunction accounts for the great majority and carries a low recurrence risk related to maternal age. Mosaicism produces a variable and often milder phenotype.

Robertsonian translocation accounts for a small minority, and here the child has 46 chromosomes with the extra 21 fused to another acrocentric chromosome. If a parent is a balanced carrier, the recurrence risk is high, which is why every child with Down syndrome should have a karyotype rather than a rapid aneuploidy test alone.

3. Sex Chromosome Disorders

Sex chromosome aneuploidies are generally milder than autosomal ones, because X inactivation limits dosage effects and the Y carries few genes.

Turner syndrome is 45,X, presenting with short stature, a webbed neck, widely spaced nipples, primary amenorrhoea from streak gonads, and coarctation of the aorta or a bicuspid aortic valve. Lymphoedema of the hands and feet may be evident at birth, and cystic hygroma in utero.

It is the one aneuploidy not associated with advanced maternal age, because it usually results from loss of a sex chromosome rather than from non-disjunction.

Klinefelter syndrome is 47,XXY, presenting after puberty with tall stature, long limbs, small firm testes, gynaecomastia and infertility. Testosterone is low and gonadotropins are high, indicating primary testicular failure.

It is the commonest genetic cause of male infertility and is frequently diagnosed only during infertility investigation, which is why karyotyping is indicated in severe male factor infertility.

4. Deletions and Microdeletions

A deletion removes a segment of chromosome, and where the segment is too small to see on a karyotype it is called a microdeletion, detected by fluorescence in situ hybridisation or chromosomal microarray.

Cri du chat syndrome results from a deletion on the short arm of chromosome 5 and is named for the characteristic high-pitched cat-like cry, with microcephaly and severe intellectual disability.

DiGeorge syndrome results from a 22q11.2 deletion and is best remembered by which embryological structures fail: the third and fourth pharyngeal pouches.

That single fact generates the whole phenotype. Thymic aplasia gives T-cell deficiency, parathyroid aplasia gives hypocalcaemia and tetany, and conotruncal cardiac defects such as tetralogy of Fallot and truncus arteriosus follow from neural crest involvement.

Williams syndrome from a 7q11.23 deletion produces supravalvular aortic stenosis, an outgoing personality, and hypercalcaemia.

Chromosomal microarray has largely replaced the karyotype as the first-line test in a child with unexplained developmental delay or multiple congenital anomalies, because it detects submicroscopic imbalances that a karyotype cannot see.

It has one important limitation: it detects copy number change, so it cannot detect balanced translocations, which is why a karyotype remains necessary when a balanced rearrangement is suspected, as in recurrent miscarriage.

5. Single Gene Disorders

Four Mendelian patterns account for most single gene disease, and the pattern predicts the recurrence risk directly.

Autosomal dominant conditions appear in every generation, affect both sexes equally, and give each child of an affected parent a one in two risk. Examples are achondroplasia, Marfan syndrome, neurofibromatosis and Huntington disease.

Autosomal recessive conditions typically appear in a single generation, affect both sexes, and give each child of two carriers a one in four risk. Consanguinity increases the frequency, which makes these conditions substantially more common in parts of India.

Examples are cystic fibrosis, sickle cell disease, thalassaemia and most inborn errors of metabolism.

X-linked recessive conditions affect males predominantly, are transmitted by carrier mothers, and are never transmitted from father to son, because a father gives his son a Y rather than an X. Examples are haemophilia A and B, Duchenne muscular dystrophy, and glucose-6-phosphate dehydrogenase deficiency.

Absence of male-to-male transmission is the single most useful pedigree observation, because it distinguishes X-linked from autosomal dominant inheritance immediately.

X-linked dominant conditions affect females more often and are lethal in males in some cases, as in Rett syndrome and incontinentia pigmenti.

Two concepts modify these patterns. Penetrance is the proportion of people with the genotype who show any phenotype, so reduced penetrance makes a dominant condition appear to skip a generation. Expressivity is how severely it is expressed among those affected, which is why neurofibromatosis varies from a few skin lesions to severe disease within one family.

6. When Mendel Does Not Apply

Three mechanisms break the standard patterns, and each is examined because of it.

Genomic imprinting means a gene is expressed from only one parental copy, so which parent contributed the abnormality determines the disease.

Prader-Willi and Angelman syndromes both involve the same 15q11-13 region and illustrate this perfectly. Loss of the paternal contribution gives Prader-Willi syndrome, with neonatal hypotonia and poor feeding followed by hyperphagia, obesity, hypogonadism and intellectual disability. Loss of the maternal contribution gives Angelman syndrome, with severe intellectual disability, ataxia, seizures and inappropriate laughter.

Mitochondrial inheritance is exclusively maternal, because the sperm contributes essentially no mitochondria to the zygote.

An affected mother therefore transmits to all her children, and an affected father transmits to none. Heteroplasmy, the coexistence of normal and mutant mitochondria, explains the variable severity, since the phenotype appears once the mutant proportion exceeds a threshold in a given tissue.

Tissues with high energy demand suffer first, which is why these disorders present with myopathy, encephalopathy, optic neuropathy and deafness.

Trinucleotide repeat expansion disorders show anticipation, meaning the disease appears earlier and more severely in successive generations, because the repeat expands as it is transmitted.

Fragile X syndrome is the commonest inherited cause of intellectual disability and is caused by CGG expansion in the FMR1 gene, producing a long face, large ears, macro-orchidism and autistic features.

Huntington disease and myotonic dystrophy are the other classical examples.

7. Screening and Diagnosis Before Birth

Screening estimates risk in a population; diagnosis establishes the answer in an individual. Confusing the two is the commonest error in this section.

Combined first trimester screening uses nuchal translucency with maternal serum markers and maternal age to generate a risk figure.

Cell-free fetal DNA testing, analysing placental DNA fragments in maternal blood, has transformed screening but remains a screening test.

Its detection rate for trisomy 21 is very high, but its positive predictive value depends on prevalence, and this is the point examiners test. The predictive value is high for trisomy 21, considerably lower for trisomy 18, and lower still for trisomy 13, simply because the rarer the condition, the greater the proportion of positives that are false.

A positive result therefore always requires confirmation by a diagnostic test, and acting on it without confirmation is a recognised cause of the termination of normal pregnancies.

Diagnostic tests obtain fetal tissue. Chorionic villus sampling is performed from around 11 weeks and carries a small risk of miscarriage. Amniocentesis is performed from around 15 weeks and remains the reference standard.

In India, disclosure of fetal sex on any of these tests is prohibited, and the legal framework is set out in the National Maternal-Child Health Programs chapter.

8. After Birth: Screening and Metabolic Disease

Newborn screening identifies conditions in which early treatment prevents irreversible damage, and the justification is always that the damage occurs before symptoms appear.

Congenital hypothyroidism is the paradigm. It is common, it is asymptomatic in the first weeks, untreated it causes permanent intellectual disability, and thyroxine started early prevents that entirely. Screening is therefore justified even where resources are limited.

Congenital adrenal hyperplasia, most often from 21-hydroxylase deficiency, presents with ambiguous genitalia in females and salt-wasting crisis in either sex, and it is a genuine neonatal emergency.

Inborn errors of metabolism should be suspected in a neonate who feeds and behaves normally at first and then deteriorates after a symptom-free interval.

That interval is the diagnostic clue, because the baby was protected in utero by the maternal circulation clearing the accumulating metabolite, and deterioration begins only after feeding starts.

Phenylketonuria causes intellectual disability, a musty odour and fair complexion, and is managed by dietary restriction. Galactosaemia presents with jaundice, hepatomegaly, cataracts and a susceptibility to Escherichia coli sepsis, and is managed by removing lactose.

9. Congenital Malformations and Teratogens

Not every congenital disorder is genetic. A malformation is a structural defect arising during organogenesis, and many are multifactorial, meaning several genes interact with an environmental exposure.

Neural tube defects are the most important because they are largely preventable. The neural tube closes by around 28 days after conception, which is often before a woman knows she is pregnant, and this timing is the whole reason folic acid must be started before conception rather than at the first antenatal visit.

Anencephaly is incompatible with life. Spina bifida ranges from occulta, often an incidental finding, through meningocele to myelomeningocele with neural tissue in the sac and consequent paralysis, bladder dysfunction and hydrocephalus.

Women with a previous affected child, on antiepileptic drugs, or with diabetes require a substantially higher folic acid dose.

A deformation differs from a malformation and the distinction is examined. A malformation is intrinsically abnormal tissue formation, whereas a deformation is normal tissue distorted by external mechanical force, as in the talipes and pulmonary hypoplasia of oligohydramnios.

A disruption is normal tissue destroyed by an external insult, as in amniotic band syndrome, and a sequence is a cascade of defects arising from one initiating problem, of which the Potter sequence following renal agenesis is the classic example.

Teratogens act during organogenesis, which runs roughly from the third to the eighth week, and exposure before that period tends to be all or nothing rather than malformation-producing.

Thalidomide causes limb reduction defects. Sodium valproate causes neural tube defects, and phenytoin a distinctive fetal hydantoin syndrome. Warfarin causes nasal hypoplasia and stippled epiphyses, and angiotensin converting enzyme inhibitors cause renal failure and oligohydramnios. Isotretinoin is a potent teratogen requiring assured contraception, and alcohol causes fetal alcohol syndrome with characteristic facies and intellectual disability.

Maternal rubella, cytomegalovirus, toxoplasmosis and syphilis are the classic congenital infections and are developed in the Paediatric Infectious Diseases chapter.

10. Worked Examples

Example 1. A child has Down syndrome. The karyotype shows 46 chromosomes with a Robertsonian translocation involving chromosome 21.

The chromosome count of 46 rather than 47 is the key, because it establishes translocation rather than free trisomy.

This changes counselling entirely. Both parents must be karyotyped, because if one is a balanced carrier the recurrence risk is substantially raised rather than the low age-related risk of free trisomy. This is precisely why every child with Down syndrome should have a full karyotype rather than a rapid aneuploidy test alone.

Example 2. A pedigree shows affected males in several generations, with transmission through unaffected females and no father-to-son transmission.

The absence of male-to-male transmission is decisive, because a father passes a Y chromosome to his son, so an X-linked condition cannot be transmitted that way.

Combined with affected males and carrier females, this is X-linked recessive inheritance. Each son of a carrier mother has a one in two chance of being affected, and each daughter a one in two chance of being a carrier.

Example 3. A cell-free DNA test reports high risk for trisomy 13. The couple ask whether the diagnosis is confirmed.

It is not. Cell-free DNA is a screening test, and its positive predictive value falls as the condition becomes rarer, so a substantial proportion of positive results for trisomy 13 are false positives.

Diagnostic testing by amniocentesis is required before any irreversible decision. The high detection rate quoted for these tests describes sensitivity, not predictive value, and conflating the two leads directly to the termination of normal pregnancies.

Summary

• Classify the error before naming the disease.
• Chromosomal errors affect many genes; single gene errors affect one protein.
• Most non-disjunction is maternal and occurs in meiosis I.
• Oocytes arrest in prophase for decades, so cohesion proteins degrade with age.
• Paternal age raises new dominant mutations, not aneuploidy.
• Aneuploidy is the commonest cause of miscarriage.
• Trisomy 21, 18 and 13 are compatible with live birth in decreasing order of survival.
• Down syndrome features hypotonia, atrioventricular septal defect and duodenal atresia.
• Early Alzheimer disease follows from three copies of the amyloid precursor gene.
• Free trisomy carries a low recurrence risk; translocation may carry a high one.
• Every child with Down syndrome needs a full karyotype, not a rapid test.
• Turner syndrome is 45,X with short stature, streak gonads and coarctation.
• Turner syndrome is not associated with advanced maternal age.
• Klinefelter syndrome is 47,XXY with small firm testes and high gonadotropins.
• Klinefelter is the commonest genetic cause of male infertility.
• DiGeorge syndrome is a 22q11.2 deletion affecting the third and fourth pouches.
• Thymic and parathyroid aplasia with conotruncal defects follow from that.
• Microarray is first line in unexplained delay or multiple anomalies.
• Microarray cannot detect balanced translocations; karyotype still can.
• Autosomal dominant gives a one in two risk to each child.
• Autosomal recessive gives one in four, and consanguinity raises frequency.
• Absence of male-to-male transmission indicates X-linked inheritance.
• Reduced penetrance makes a dominant condition appear to skip a generation.
• Expressivity explains variable severity within one family.
• Imprinting means which parent contributed the defect determines the disease.
• Prader-Willi loses the paternal contribution; Angelman the maternal.
• Mitochondrial inheritance is exclusively maternal.
• Heteroplasmy explains variable severity through a threshold effect.
• Trinucleotide repeat disorders show anticipation as the repeat expands.
• Fragile X is the commonest inherited cause of intellectual disability.
• Neural tube closure by 28 days is why folic acid must precede conception.
• Malformation is abnormal formation; deformation is normal tissue distorted by force.
• A disruption destroys normal tissue; a sequence cascades from one initiating defect.
• Potter sequence follows renal agenesis.
• Teratogens act during organogenesis, roughly weeks three to eight.
• Valproate causes neural tube defects; warfarin causes stippled epiphyses.
• Screening estimates risk; diagnosis establishes the answer.
• Cell-free DNA predictive value falls as the condition becomes rarer.
• A positive cell-free DNA result always requires diagnostic confirmation.
• Chorionic villus sampling from 11 weeks; amniocentesis from 15.
• Congenital hypothyroidism is the paradigm for newborn screening.
• A symptom-free interval then deterioration suggests an inborn error.
• The interval exists because the maternal circulation cleared the metabolite in utero.