MRCPCH GUIDE Genetics

Parents who have had one affected child have a 35% risk in future pregnancies of having another
affected child. In conditions inherited in a multi-factorial fashion
Alpha thalassemia, chromosome 16p and Sickle cell disease, chromosome 11p are correctly
paired. The correct associations for the remaining conditions would be: Tuberose sclerosis,
chromosome 9q, Polyposis coli, chromosome 5q and Phenylketonuria, chromosome 12q.
Alagille syndrome comprises biliary hypoplasia, arteriohepatic dysplasia,
hyperbilirubinaemia and vertebral and cardiac anomalies. Fifteen per cent of cases are
autosomally dominant inherited with variable expression. Autosomal recessive inheritance
and sporadic mutations are also found. It involves the deletion of p20 (jag 1) gene. A total of
20% of cases are premature/intrauterine growth retardation or small or small for gestational
age infants. The aetiological factor may be a viral teratogenic factor.
Typical facial appearances include frontal bossing, a pointed chin, deepset eyes and a
prominent nose. Ophthalmological findings include posterior embryotoxin (70%) and
pseudo-retinitis. Butterfly vertebrae (50%) are the known bony defects. Congenital heart
disease is seen in 95% of cases, 10% of whom have cyanotic conditions and 50% of whom
are known to have peripheral pulmonary artery stenosis. Liver complications include chronic
cholestasis (paucity of the interlobar ducts), obstructive jaundice (often diagnosed when an
infant), giant-cell hepatitis, pruritis and loose pale stools after the introduction of a fat-laden
diet. Other clinical manifestations include learning difficulties, delayed sexual development
and endocrine, neurological and renal abnormalities. The family cardiac history includes
atrioventricular septal defect, hypoplastic left heart (HLH) and right ventricular outflow tract
obstruction syndrome.
Diagnosis is aided by a HIDA liver isotope scan. Other useful tests include liver biopsy to
exclude biliary atresia, ophthalmic assessment to review the cornea, cardiac assessment, a
spinal radiograph to visualise the vertebral axis, a sweat test to exclude cystic fibrosis and
finally a genetics assessment. The differential diagnoses include extrahepatic biliary atresia,
hepatitis syndrome, hepatic thrombosis, cystic fibrosis, galactosaemia, tyrosinaemia and
Zellweger syndrome. The prognosis is satisfactory for 2025% of cases, but the mortality rate
due to liver failure is 3%.

Fetal rubella infection is not associated with limb defects. Fetal infection following maternal
infection with rubella is maximum in the first two months with a declining incidence up to the fifth
month. Deafness is the most frequent clinical complication incidence ranges from 83% of infants
exposed in the first month to 49% in the fourth month. After the fourth month the risk of deafness
declines. Congenital heart disease, particularly patent ductus arteriosus (PDA) and peripheral
pulmonary stenosis, affects around 50% of infants. Other complications include microcephaly,
mental retardation, cataract, chorioretinitis and mental retardation. Fanconis anaemia and Holt
Oram syndrome are associated with radial ray defects. Fetal vitamin A syndrome can present with
bony defects, absent thumbs, syndactyly and camptodactyly. Amniotic bands commonly present
with terminal amputations and constriction bands.

Fluorescence in situ hybridisation (FISH) is a special staining technique to visualise chromosome
segments of interest. The specimen is processed and the slides are prepared in the usual manner.
The chromosomes are denatured (ie, DNA which is normally a double helix is rendered single-
stranded) and a single-stranded DNA probe, that matches the segment of DNA on the
chromosome that is thought to be missing, is added on the slide. Annealing (attachment) takes
place between the single-stranded probe and its complementary sequences on the single-stranded
chromosomes. The excess probe is washed away and the slide is treated with other agents to
permit visualisation of the probe using fluorescence microscopy. G-banding remains the primary
method of staining for routine chromosome analysis, as it is less expensive than FISH.

In neurofibromatosis type 2, cataracts can occur. Early detection in family members may be made
by finding lens opacities (both congenital polar cataracts and posterior lenticular opacities).
However cataracts are not seen in NF1. The eye findings in NF1 are Lischs nodules, which are
pigmentary lesions seen on the iris and constitute one of the major diagnostic features in this
condition.
Incontinentia pigmenti is an X-linked dominant disorder with pigmentary skin changes, mental
retardation and eye involvement in 40% of cases. Myotonic dystrophy is a triplet-repeat disorder
with neurological symptoms and cataracts. Lowes syndrome (oculo-cerebro-renal syndrome) is an
X-linked recessive condition. Males with this X-linked recessive condition have cataracts,
hypotonia, mental retardation, a generalised aminoaciduria and renal tubular acidosis with
hypophosphatasia. Wilsons disease is an inborn error of copper metabolism. The clinical features
include hepatic involvement, progressive neurological features, eye involvement including Kayser
Fleischer rings and cataracts.

Gonadal mosaicism
Very rarely, two or more sibs with an autosomal dominant trait have normal parents. This can be
explained on the basis of germ-line or gonadal mosaicism. A parent could have a mutation that is
limited to the germ-line (germ cells egg or sperm) while sparing the somatic cells. Such
individuals are phenotypically normal; however, they have a greater risk of recurrence than the
general population. This phenomenon has been described in osteogenesis imperfecta,
achondroplasia and Duchennes muscular dystrophy.

Burkitts lymphoma
90% have a 8/14 translocation or 8/2 or 8/22. Chromosomes 2,14, 22 carry Ig genes and an
oncogene is on chromosome 8.

Marfans syndrome
15% spontaneous mutation rate. Fibrillin gene chromosome 15q.

Noonans is an autosomal dominant disorder often caused by mutation in PTPN11.

Prader Willi Syndrome
A microdeletion is present in about 70%.

Approximately 1/3 of individuals with Turners syndrome have a thyroid disorder, usually
hypothyroidism.

There are a number of different causes of ambiguous genitalia.
True hermaphroditism - children have both ovarian and testicular tissues and external
genitalia that are partially ambiguous (46, XX, 46, XY, or mosaic).
Gonadal dysgenesis - children have an undeveloped gonad, usually female internal sex
organs and external genitals that may vary between normal female and normal male,
with the majority female. Chromosomes that are 45, X, 46, XY, 46, XX, or mosaic.
Pseudohermaphroditism - children who have questionable external genitalia, but have
only one gender's internal reproductive organs. Male pseudohermaphroditism may be
caused by Androgen insensitivity syndrome (children have 46, XY karyotype and normal
female external genitalia.) or 5-alpha-reductase deficiency (children who have genital
ambiguity and 46, XY karyotype). Female pseudohermaphroditism may be due to
Congenital adrenal hyperplasia or other causes of increased testosterone (eg. Maternal
drug treatment ).


Fraternal twins (non-identical) usually occur when two fertilised eggs are implanted in the uterine
wall at the same time. The two eggs form two zygotes, and these twins are therefore also known
as dizygotic. Dizygotic twins may be a different sex or the same sex, just as with any other siblings.
The risk of autosomal recessive disorders in a dizygotic twin of an affected child is (as with other
siblings).
Identical twins occur when a single egg is fertilised to form one zygote (monozygotic) but the
zygote then divides into two separate embyros. Monozygotic twins are genetically identical unless
there has been a mutation in development, and they are almost always the same gender. The two
embryos develop into fetuses sharing the same womb. Depending on the stage at which the
zygote divides, identical twins may share the same amnion (in which case they are known as
monoamniotic) or not (diamniotic). Diamniotic identical twins may share the same placenta
(known as monochorionic) or not (dichorionic). Sharing the same amnion (or the same amnion and
placenta) can cause complications in pregnancy. For example, the umbilical cords of
monoamniotic twins can become entangled, reducing or interrupting the blood supply to the
developing fetus. Monochorionic twins, sharing one placenta, usually also share the placental
blood supply. These twins may develop such that blood passes disproportionately from one twin
to the other through connecting blood vessels within their shared placenta, leading to twin-to-
twin transfusion syndrome. About 50% of mono-mono twins die from umbilical cord
entanglement.

Mitochondrial DNA
This condition is inherited in an X-linked dominant pattern.

genetic anticipation
Such dynamic mutations form the basis of an increasing list of inherited neurologic disorders
that includes mental retardation (fragile X syndrome), myotonic dystrophy, oculopharyngeal
muscular dystrophy, Friedreich ataxia, Huntington disease, and the dominantly inherited
cerebellar ataxias.

Alpha thalassemia, chromosome 16p and Sickle cell disease, chromosome 11p are correctly
paired. The correct associations for the remaining conditions would be: Tuberose sclerosis,
chromosome 9q, Polyposis coli, chromosome 5q and Phenylketonuria, chromosome 12q.
Marfans syndrome is inherited in an autosomal dominant manner, with the gene locus on
chromosome 15.

Treacher Collins syndrome has autosomal dominant inheritance. It is a 1
st
branchial arch
defect. Deafness, coloboma (mainly of the lower eyelids), recurrent ear infections and cleft
palate are all recognised features, along with ventricular septal defects and fusion of the radius
and ulna.

Noonan syndrome is a common autosomal dominant condition, caused by mutations in PTPN11
on chromosome 12q. The incidence is around 1 in 2500 individuals. Affected individuals are
characteristically short (mean height around 3
rd
centile), and have down slanting palpebral
fissures, with heavy or hooded eyelids. A low posterior neckline and short webbed neck are
often seen.
50-80% of individuals with Noonan syndrome have a cardiac defect. The most common defect is
pulmonary stenosis. Hypertrophic cardiomyopathy occurs in about 20% of individuals with
Noonan syndrome, and may present throughout life. Feeding problems in infancy are very
common, and this appears to correlate with mild developmental delay (seen in about 30% of
cases). Feeding difficulties occur in the majority, and NG feeding is often necessary.
Developmental delay may bee seen early in life, but IQ is usually in the normal range, and the
majority are educated in mainstream school. In children with Noonan syndrome, problems
with coagulation are common, and this should be investigated if a history of easy bruising or
abnormal bleeding is seen in childhood.

One main gene for Rett syndrome has been found MECP2, located on Xq28. More than 99% of
cases are de novo occurrences.

Klinefelter syndrome results from a 47XXY karyotype. It has a prevalence of 1/600-1/800 male
births. It is more common with increasing maternal age. Babies appear normal at birth, but in
childhood are taller than their peers. A tendency towards passive, unassertive behaviour has
been noted frequently. Although boys enter puberty normally, by mid-puberty the testes begin
to involute and they develop hypergonadotrophic hypogonadism with decreased testosterone
production. 47, XXY males are, with occasional exceptions, infertile. Gynaecomastia is
common, and occasionally requires surgical reduction. Congenital heart disease is not a
feature of Klinefelter syndrome.

A child comes to see you for investigation of hyperphagia. At birth, he was extremely floppy
and he required NG feeding for the first 6 months of life due to a poor suck.
Uniparental disomy Your answer
Sporadic occurrence Correct answer
Sporadic occurrence
The condition described is Prader-Willi syndrome. It results from absence of
transcription of paternally inherited genes on chromosome 15. 70% of cases are
sporadic. Most of the other 30% are caused by uniparental disomy (inheritance of both
maternal alleles).
Congenital myotonic dystrophy
Myotonic dystrophy is the most common inherited neuromuscular disorder, with a prevalence of
1/8000. It is inherited in an autosomal dominant manner, and severity depends on the size of
expansion within the myotonin gene on chromosome 19. Most affected individuals have muscle
weakness and myotonia, together with cataracts and diabetes mellitus. Congenital myotonic
dystrophy is likely to occur when an affected mother has an affected baby. The resulting problems
are severe muscle weakness and respiratory problems in the infant.
Crohns disease does not appear to be more common in individuals with DS. Coeliac disease
does have a higher prevalence. Atlanto-axial subluxation occurs in 12-20 % of individuals with
DS although symptoms are rare. At least 40% of individuals with DS develop Alzheimers later in
life. This may result from a gene dosage effect for the amyloid precursor gene on chromosome
21.
Downs syndrome is associated with an increased incidence of leukaemia, Alzheimers disease and
duodenal atresia and atlanto-axial dislocation. It is also associated with an increased risk of
congenital heart disease (In Downs syndrome cardiac lesions are present in 30-50% of children.
The most common lesions are septal defects, 30% being atrioventricular septal defects and 30%
being ventricular septal defects). They also are at risk of oesophageal atresia, Hirschprungs
disease, pulmonary hypertension and cataracts.
Neonatal hypotonia is an almost universal feature of Downs syndrome. Cardiac lesions are
present in 30-50% of children. The most common lesions are septal defects, 30% being
atrioventricular septal defects and 30% being ventricular septal defects. Downs syndrome is
associated with an increased incidence of hypothyroidism, cervical spine abnormalities,
leukaemia, Alzheimers disease, duodenal and oesophageal atresia, Hirschprungs disease,
pulmonary hypertension and cataracts. The majority of cases arise from chromosomal non-
dysjunction at meiosis. Although it is important to examine the karyotype for translocations (as
inheritance from either parent increases the risks for future pregnancies), translocations are
found in fewer than 5% of children with trisomy 21.

Klinefelters Syndrome has a karyotype of 47XXY. It is usually due to meiotic
non-dysjunction. Increased maternal age is a risk factor. Affected men are tall
and thin with bilateral gynaecomastia, delayed puberty and hypogonadism
leading to infertility. Intelligence tends to be below average.
Microcephaly refers to a small head, where the head circumference is less than 2 standard
deviations below the mean. Microcephaly can be primary or secondary to other causes. Primary
causes include genetic defects such as trisomy 13,18 and 21 and Cri du Chat syndrome (5p-).
Secondary microcephaly occurs due to congenital infections, placental insufficiency, maternal
alcohol consumption during pregnancy and hypoxic ischaemic encephalopathy. Sotos syndrome is
a state of cerebral gigantism and thus macrocephaly.

Neurofibromatosis type I is associated with optic gliomas (15%) and Lisch iris nodules. It is an
autosomal dominant condition with the gene locus on chromosome 17. At least 50% of cases arise
due to new mutations. Other features include axillary freckling, 6 or more caf au lait spots and
bony lesions such as kyphoscoliosis. Neurofibromatosis type II is associated with bilateral acoustic
neuromas. It is an autosomal dominant condition with the gene locus on chromosome 22.

Di George syndrome is associated with chromosome 22q11.2 deletion. It arises due to a defect in
embryological development of the 3
rd
and 4
th
pharyngeal arches, which consequently affects the
development of the thymus, parathyroid glands and the heart tube. This can lead to abnormalities
of the thymus, hypoparathyroidism (therefore low calcium) and heart- such as interrupted aortic
arch, truncus arteriosus, tetralogy of fallot and familial VSD. Ear abnormalities are also recognised.

Sickle cell disease is associated with a gene defect on chromosome 11p, cystic fibrosis with a gene
defect on chromosome 7p and neurofibromatosis with defects on chromosome 17 (type I) and 22
(type II). Myelomeningocele does not have a specific gene locus and Klinefleters syndrome occurs
due to the karyotype 47XXY.
Polyhydramnios is associated with an amniotic fluid volume in excess of
2000ml. Causes include Oesophageal atresia, Anencephaly, duodenal or Jejunal
atresia, maternal diabetes mellitus, fetal anaemia, hydrocephalus and spina
bifida. Posterior urethral valves and renal agenesis are associated with
oligohydramnios.

fragile X syndrome
Boys with the FMR1 full mutation are always affected (unless they have coincidental
Klinefelter syndrome). Girls with the full mutation have around a 50% chance of showing
significant learning disability or behavioural features. The sons of a woman with full
mutation have a 50% chance of inheriting a normal X chromosome, in which case they would
be unaffected. There is also a 50% chance they would inherit the full mutation (which rarely
contracts in size) and so be affected. Pre-mutation carriers of either sex are not affected. A
man passes on his Y chromosome to all his sons. He passes his X chromosome to all his
daughters, but the pre-mutation does not expand when transmitted through a male, which
means that all his daughters will be pre-mutation carriers. In the past, testing was cytogenetic
and required culturing of lymphocytes in folate-deficient media to reveal the fragile site.
However, this resulted in false-negatives. Modern testing is by molecular genetic analysis to
assess the size of the repeat expansion, which is far more reliable.
Imprinted genes are those for which the parental origin determines the degree to which they are
expressed. Imprinting can involve exclusive expression of one parental allele, or relatively greater
expression from one allele compared to another. The pattern of parental expression is consistent
across all normal individuals. Imprinting of some genes is tissue specific (that is, it can only be
detected in certain tissues). BeckwithWiedemann syndrome results from abnormal imprinting of
the IGF2/H19/KVLQT1/p57kip (CDKN1C) gene cluster on chromosome 11p15, although there are
several different underlying molecular mechanisms. PraderWilli syndrome results from absence of
a paternal contribution for genes on chromosome 15q1113. In around 70% it is due to a deletion
on the paternal-derived chromosome 15 while in about 30% it is due to maternal uni-parental
disomy for chromosome 15 (where both copies of chromosome 15 are maternally derived with no
paternal contribution). Transient neonatal diabetes results from abnormal imprinting of a gene(s) on
distal chromosome 6q. Most patients have been found to have paternal uni-parental disomy for the
region or paternal duplications. Around 15% of patients with SilverRussell syndrome have maternal
uni-parental disomy for chromosome 7. In the remainder, the molecular mechanism is not yet clear.

FISH testing is used to detect sub-microscopic chromosome deletions (microdeletions).
Patients with Williams syndrome have deletions which encompass the elastin gene and
adjacent genes, DiGeorge syndrome results from 22q11 deletions, and cri-du-chat results
from deletions of chromosome 5p, which may be visible on standard microscopy but may be
sub-microscopic (therefore it is best tested for by FISH). Although FISH testing will detect
patients with PraderWilli who have a deletion (around 70%) it does not detect the 30% of
patients with uni-parental disomy. Molecular genetic (DNA-based) testing is now used for
Prader-Willi which screens for both. In translocation Down syndrome, the translocation is
best seen on routine karyotyping.