Learn — Genetics: chromosomes, inheritance, disorders & counselling

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Karyotype, meiosis and patterns of inheritance — Mendelian, X-linked and pedigree

Medical genetics begins with the 46 chromosomes of the human karyotype — 22 pairs of autosomes and the sex chromosomes XX or XY — the meiosis that halves them into the gametes and mixes the parents' genes by crossing over, and the patterns by which a single gene's alleles pass from parent to child: autosomal dominant, autosomal recessive, X-linked recessive and the rarer X-linked dominant, Y-linked and mitochondrial patterns, with multifactorial inheritance for the common disorders that run in families without a single gene. The paper asks the karyotype notation, the Barr body, Mendel's laws and, above all, which named disease follows which pattern and with what risk to the next child; the nurse needs the same to draw a pedigree and to answer the mother who is being blamed for the sex of her daughter.

A karyotype is the chromosomes of a dividing cell arrested in metaphase, stained (Giemsa banding), photographed and arranged in pairs by size; it is written as the total number and the sex chromosomes — 46,XX or 46,XY normal, 47,XY,+21 Down syndrome, 45,X Turner, 47,XXY Klinefelter — and is ordered for ambiguous genitalia, recurrent miscarriage, infertility, a suspected chromosomal syndrome, and leukaemia (the Philadelphia chromosome); the Barr body is the inactivated X chromosome seen against the nuclear membrane in a buccal smear (Lyon's hypothesis), and its number is one fewer than the number of X chromosomes — none in a normal male, one in a normal female, one in Klinefelter.
Mitosis makes two identical cells with 46 chromosomes for growth and repair; meiosis makes four gametes with 23 through two divisions, and in its first prophase the homologous chromosomes exchange segments (crossing over), which with independent assortment is the source of variation; non-disjunction — the failure of a pair to separate — produces a gamete with 24 or 22 chromosomes and, after fertilisation, a trisomy or a monosomy, and because the oocyte waits in the first meiotic prophase from fetal life until ovulation, the risk of non-disjunction rises with maternal age.
Sex is decided by the sperm: the SRY gene on the Y chromosome makes the testis, an X-bearing sperm makes a daughter and a Y-bearing sperm a son, and the mother contributes an X to every child — the fact that answers the family that blames a woman for her daughters; the chromosomal sex, the gonadal sex, the phenotypic sex and the gender may not agree, which is the field of the disorders of sex development.
The vocabulary: a gene at a locus has alleles; a person is homozygous with two identical alleles or heterozygous with different ones; the genotype is the alleles, the phenotype the visible result; a dominant allele shows in the heterozygote and a recessive only in the homozygote; penetrance is the proportion of carriers who show the trait, expressivity the degree to which they show it, codominance the expression of both alleles (blood group AB), pleiotropy one gene with many effects (Marfan), anticipation the earlier and more severe disease in each generation from expanding trinucleotide repeats (Huntington's, myotonic dystrophy, fragile X); Mendel's laws are segregation (the two alleles separate into different gametes), independent assortment and dominance, and the Punnett square draws the risk.
Autosomal dominant inheritance: the trait appears in every generation (vertical transmission), affects both sexes equally, passes from an affected parent to half the children on average, and a new mutation can start it in a family (achondroplasia, with paternal age); the diseases are Huntington's disease, Marfan syndrome, achondroplasia, adult polycystic kidney disease, neurofibromatosis, familial hypercholesterolaemia, hereditary spherocytosis, osteogenesis imperfecta, familial adenomatous polyposis, myotonic dystrophy and the BRCA cancers.
Autosomal recessive inheritance: the parents are healthy carriers, the trait appears in siblings (horizontal transmission) with a one-in-four risk in each pregnancy, two in four carriers and one in four unaffected non-carriers, both sexes equally, and consanguinity raises the risk because cousins share the rare allele; the diseases are sickle cell disease, the thalassaemias, cystic fibrosis, phenylketonuria, galactosaemia, albinism, congenital adrenal hyperplasia, Wilson's disease, Tay-Sachs disease and most inborn errors of metabolism — the reason a marriage between first cousins is a genetic counselling indication.
X-linked recessive inheritance: the gene is on the X, so males with one X are affected and females with two are usually carriers; a carrier mother passes the disease to half her sons and the carrier state to half her daughters, an affected father passes it to none of his sons (they get his Y) and the carrier state to all his daughters, and there is never male-to-male transmission — haemophilia A and B, Duchenne and Becker muscular dystrophy, G6PD deficiency, red-green colour blindness and Hunter's syndrome; X-linked dominant disease (vitamin D-resistant rickets, Rett syndrome) affects both sexes and passes from an affected father to all his daughters and none of his sons; Y-linked traits pass father to son; mitochondrial disease (MELAS, Leber's optic neuropathy) passes from the mother to all her children and from a father to none; and multifactorial or polygenic disorders — cleft lip and palate, neural tube defects, pyloric stenosis, congenital heart disease, diabetes, hypertension, schizophrenia — cluster in families with a recurrence risk of about 2 to 5 per cent for a sibling, rise with the number affected and with severity, and are the disorders folic acid and glucose control can prevent; on a pedigree a square is a male, a circle a female, a shaded symbol affected, a half-shaded symbol a carrier, a double line consanguinity, a diagonal line deceased and an arrow the proband.

Chromosomal and single-gene disorders — Down, Turner, Klinefelter and the Mendelian diseases

The chromosomal disorders are the diseases of an extra, missing or rearranged chromosome — Down, Edwards and Patau syndromes from an extra autosome, Turner and Klinefelter syndromes from a missing or extra sex chromosome, and the deletion syndromes — and the single-gene disorders are the diseases of one mutant gene inherited by a Mendelian pattern, from the thalassaemias and sickle cell disease to haemophilia, Duchenne dystrophy, cystic fibrosis and phenylketonuria. The paper asks the karyotype, the features and the complications of each, and the teratogens that mimic them; the nurse recognises the newborn with the flat face and the single palmar crease, sends the echocardiogram that saves him, and tells the parents the truth kindly.

Down syndrome (trisomy 21) is the commonest chromosomal disorder and the commonest genetic cause of intellectual disability, about 1 in 700 to 800 births: 95 per cent are from maternal non-disjunction (the risk rises from about 1 in 1000 at 30 to 1 in 100 at 40 and 1 in 30 at 45), about 4 per cent from a Robertsonian translocation (which can be carried by a parent and recurs — the parents must be karyotyped) and 1 per cent are mosaics; the features are hypotonia, a flat face and occiput, upslanting palpebral fissures with epicanthic folds, Brushfield spots in the iris, a protruding tongue, low-set ears, a single transverse palmar crease, a short incurved little finger, a wide sandal gap between the toes and short stature.
The complications of Down syndrome are what the nurse screens for: congenital heart disease in 40 to 50 per cent (atrioventricular septal defect above all, then ventricular septal defect — every baby has an echocardiogram), duodenal atresia and Hirschsprung's disease (bilious vomiting, delayed meconium), hypothyroidism, leukaemia at 10 to 20 times the risk, hearing and vision defects, obstructive sleep apnoea, atlantoaxial instability (care with the neck under anaesthesia and in sport), recurrent infections, an intelligence quotient usually of 25 to 50 with a warm sociable temperament, and early Alzheimer's disease; the screening tests in pregnancy are on the prenatal-diagnosis note.
The other trisomies die early: Edwards syndrome (trisomy 18) with a small jaw, low-set ears, clenched fists with overlapping fingers, rocker-bottom feet and a ventricular septal defect; Patau syndrome (trisomy 13) with cleft lip and palate, polydactyly, microcephaly and holoprosencephaly; the deletion syndromes are cri-du-chat (5p deletion — the cat-like cry, microcephaly), and the imprinting pair on 15q — Prader-Willi from the paternal deletion (hypotonia, then obesity and insatiable hunger) and Angelman from the maternal (the happy, laughing, ataxic child); fragile X syndrome, the commonest inherited intellectual disability, is a CGG repeat expansion on the X with a long face, large ears, large testes after puberty and autism.
The sex-chromosome disorders: Turner syndrome (45,X — about 1 in 2500 girls) gives short stature, a webbed neck, a low hairline, a shield chest with widely spaced nipples, cubitus valgus, lymphoedema of the hands and feet at birth, streak ovaries with primary amenorrhoea and infertility, coarctation of the aorta and a bicuspid aortic valve, horseshoe kidney and normal intelligence, and is treated with growth hormone and oestrogen; Klinefelter syndrome (47,XXY — about 1 in 500 to 1000 boys) is the commonest cause of male hypogonadism, with tall stature and long limbs, small firm testes, gynaecomastia, azoospermia and infertility, mild learning difficulty and a Barr body in a male, treated with testosterone; XYY men are tall and fertile, and triple-X women are usually normal.
The single-gene disorders the Indian nurse meets most: beta-thalassaemia major (autosomal recessive; about 3 to 4 per cent of Indians carry it — a carrier has a low MCV with a raised haemoglobin A2 above 3.5 per cent; the child is transfusion-dependent from the first year, with Cooley's facies, hepatosplenomegaly, iron overload needing chelation, and prenatal diagnosis by chorionic villus sampling when both parents carry), sickle cell disease (autosomal recessive; the tribal belts of central and western India; painful vaso-occlusive crises, acute chest syndrome, stroke, autosplenectomy and infection; hydroxyurea, penicillin prophylaxis and the national elimination mission's screening), and haemophilia A and B (X-linked recessive, on the bleeding-disorders note).
The rest of the Mendelian list: Duchenne muscular dystrophy (X-linked recessive, dystrophin; a boy who cannot run at 3 to 5 years, Gowers' sign, calf pseudohypertrophy, a very high creatine kinase, a wheelchair by 12 and cardiomyopathy); cystic fibrosis (autosomal recessive, CFTR; meconium ileus, recurrent chest infections, pancreatic insufficiency and a sweat chloride above 60 mmol/L); phenylketonuria (autosomal recessive; a mousy smell, fair skin and eczema, intellectual disability unless a low-phenylalanine diet starts in the first weeks — the newborn screening test); galactosaemia (cataract, hepatomegaly and Escherichia coli sepsis — no lactose); congenital adrenal hyperplasia (ambiguous genitalia in a girl, salt-wasting collapse in the second week); Marfan syndrome (autosomal dominant; tall, arachnodactyly, upward lens dislocation, aortic dissection); achondroplasia (autosomal dominant, usually a new mutation); Huntington's disease (autosomal dominant, chorea and dementia at 30 to 50); neurofibromatosis type 1 (six or more café-au-lait spots, neurofibromas, Lisch nodules); osteogenesis imperfecta (blue sclerae and fractures); and the hereditary spherocytosis, familial hypercholesterolaemia and polycystic kidney disease of the dominant list.
Teratogens mimic genetic disease and are preventable: the organs form between the third and eighth weeks, so exposure then does the most harm, and before two weeks the effect is all or nothing; alcohol (fetal alcohol syndrome — the smooth philtrum, thin upper lip and short palpebral fissures, microcephaly, growth restriction and the commonest preventable cause of intellectual disability), thalidomide (phocomelia), phenytoin (the fetal hydantoin face and nails), valproate and carbamazepine (neural tube defects), warfarin (nasal hypoplasia and stippled epiphyses — heparin replaces it), isotretinoin and high-dose vitamin A (craniofacial and cardiac defects), ACE inhibitors (renal failure), tetracycline (stained teeth), aminoglycosides (deafness), lithium (Ebstein's anomaly), methotrexate, androgens, diethylstilboestrol (vaginal adenocarcinoma in the daughter decades later), radiation, hyperthermia, maternal diabetes (caudal regression and heart defects) and the TORCH infections — rubella above all, with cataract, deafness and patent ductus arteriosus.

Prenatal diagnosis, newborn screening, genetic counselling and the PCPNDT Act

Prenatal diagnosis is the detection of a genetic or structural disorder in the fetus — by screening tests that estimate risk without harm and by invasive tests that give an answer at a small risk of miscarriage — so that the family can prepare, treat or, within the law, end the pregnancy; newborn screening finds the treatable inborn disorders in the first days of life before they do damage; and genetic counselling is the non-directive communication of risk and options that makes both meaningful. In India all of this stands under the Pre-Conception and Pre-Natal Diagnostic Techniques Act, which permits the tests for their medical purposes and criminalises the one use — sex selection — that has cost the country millions of daughters.

Indications for prenatal diagnosis: maternal age of 35 years or more, a previous child with a chromosomal or single-gene disorder, a parent who carries a balanced translocation or a single-gene disorder (both parents thalassaemia carriers is the commonest Indian indication), a positive screening test, an abnormality on ultrasound, exposure to a teratogen, consanguinity with a family history, recurrent miscarriage and a family history of X-linked disease.
Screening tests carry no risk to the pregnancy and give a risk, not a diagnosis: the first-trimester combined test at 11 to 13 weeks and 6 days — nuchal translucency of 3 mm or more on ultrasound with low pregnancy-associated plasma protein A and high free beta-hCG in Down syndrome; the quadruple test at 15 to 20 weeks — alpha-fetoprotein, hCG, unconjugated oestriol and inhibin A, with low AFP and oestriol and high hCG and inhibin in Down syndrome, and a high AFP in neural tube defects, abdominal wall defects, twins and wrong dates; non-invasive prenatal testing on cell-free fetal DNA in the mother's blood from 10 weeks, more than 99 per cent sensitive for trisomy 21 but still a screen; and the anomaly scan at 18 to 20 weeks for structural defects and soft markers.
Diagnostic tests are invasive and give an answer: chorionic villus sampling at 10 to 13 weeks (placental tissue for karyotype and DNA; about 1 per cent miscarriage; limb defects if done before 10 weeks; placental mosaicism can mislead), amniocentesis at 15 to 20 weeks (amniotic fluid cells for karyotype and DNA, fluid for alpha-fetoprotein and acetylcholinesterase; 0.5 to 1 per cent miscarriage; anti-D for the Rh-negative mother; a full karyotype takes two to three weeks and a rapid FISH or PCR result days), cordocentesis from 18 weeks (fetal blood for haemoglobin, karyotype and infection; 1 to 2 per cent loss), fetal echocardiography, and pre-implantation genetic diagnosis of embryos before transfer in in-vitro fertilisation for families with a known mutation.
Newborn screening is a heel-prick at 48 to 72 hours on a filter-paper card for the disorders that are silent at birth and treatable — congenital hypothyroidism (the commonest and the most rewarding: thyroxine before the brain is damaged), phenylketonuria, galactosaemia, G6PD deficiency, congenital adrenal hyperplasia, cystic fibrosis and the haemoglobinopathies — with hearing screening by otoacoustic emissions; India has no universal programme yet, but the Rashtriya Bal Swasthya Karyakram screens every child from birth to 18 years for the four Ds — defects at birth, deficiencies, diseases and developmental delays — through its mobile teams and District Early Intervention Centres, and the National Sickle Cell Anaemia Elimination Mission (2023) screens the tribal populations and issues cards.
Genetic counselling is a communication process about the occurrence and risk of a genetic disorder in a family: a three-generation pedigree and the diagnosis, the risk estimated from the Mendelian pattern or the empirical tables, the options explained — prenatal diagnosis, termination within the Medical Termination of Pregnancy Act (up to 20 weeks on one doctor's opinion, 20 to 24 weeks on two for the categories the 2021 amendment names, and beyond 24 weeks on a Medical Board's opinion for substantial fetal abnormality), preparation for an affected child, adoption, donor gametes — and the family supported in the decision that is theirs; it is voluntary, confidential, truthful and non-directive, and the counsellor's own view is not part of it.
The nurse's part is to find the family before the counsellor does — the consanguineous couple, the mother over 35, the previous affected child, the recurrent miscarriages, the teratogen exposure, the carrier state on the antenatal blood — to refer and to coordinate the tests, to counsel on folic acid before conception and the avoidance of teratogens, to support the decision without steering it, and to end the blame: the sex of the child comes from the father's sperm, a recessive disease comes from both parents, and a non-disjunction comes from no one's act.
The Pre-Conception and Pre-Natal Diagnostic Techniques (Prohibition of Sex Selection) Act, 1994, amended in 2003, forbids sex selection before or after conception and the determination or communication of the sex of the fetus by any means — 'by words, signs or in any other manner' — regulates every genetic counselling centre, laboratory and clinic and registers every ultrasound machine, allows prenatal diagnostic tests only for the listed indications (maternal age over 35, a previous child with a genetic or chromosomal abnormality, exposure to teratogens, a family history of genetic disease and the conditions the Board specifies) with a written consent, requires the records to be kept for two years, punishes the doctor with three years' imprisonment and a fine on the first offence and five years on the next, presumes that the woman was compelled and does not punish her, and is enforced by the Appropriate Authority in every district; the child sex ratio of 918 girls per 1000 boys in Census 2011 and the sex ratio at birth of 918 in the Sample Registration System (2022-24) are the reason it exists, and a nurse who hints at the sex of a fetus has broken it.

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