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Paediatrics: Genetic testing in cognitive impairment

Amongst children with severe mental retardation, a high proportion will have a genetic cause.

Genetic testing in cognitive impairment


Amongst children with severe mental retardation, a high proportion will have a genetic cause. This can be elucidated in 750% of children, with chromosomal disorders being the largest group. Referral to clinical genet-ics should be considered for all children with unexplained severe global developmental delay/mental retardation.


The referring paediatrician may undertake some basic diagnostic genetic testing, including the following:


   Chromosome analysis: investigation with the highest yield for children with unexplained developmental delay. Specific FISH tests for submicroscopic microdeletions, e.g. Williams, 22q11 syndrome, can also be requested.

   Fragile X analysis: this is the commonest cause of inherited learning disability, but remains a rare disorder. As it is often difficult to diagnose on clinical grounds, genetic testing should be offered to all children with developmental delay.

   Creatine kinase in boys: DMD may present with speech delay and delayed motor milestones and/or global delay.

   Thyroid function tests: children born in the UK should have been tested for congenital hypothyroidism on the newborn blood spot screen. If this result was normal (need confirmation), repeat investigation is not required unless there are clinical signs suggestive of hypothyroidism.

   Amino and organic acids: inborn errors of metabolism are individually rare, but may present with non-specific features, e.g. developmental delay and/or FTT. Plasma and urine samples should be arranged if there is developmental regression, episodic decompensation, parental consanguinity, a family history, or physical examination findings consistent with a metabolic disorder, e.g. microcephaly, macrocephaly, hepato-splenomegaly. ‘Non-specific’ abnormalities are more common than true diagnoses.

   Urine glycosaminoglycans (mucopolysaccharidoses): consider if developmental regression, glue ear, coarse features, macrocephaly.

   Ophthalmological opinion: especially if there is concern regarding vision, eye signs (e.g. nystagmus), neurological signs, microcephaly.

   Audiology assessment: especially if there is speech delay or concern regarding hearing.

   Consider congenital infection: in children with intrauterine growth retardation, microcephaly, and eye/hearing signs. Requires comparison of maternal booking and current maternal serology. Useful for children up to 718 months of age.


See M www.phgfoundation.org/pages/work.htm.

Angelman syndrome (AS)


·Incidence 71/40 000.

AS is caused by impaired or absent function of the maternally imprinted UBE3A gene on chromosome 15q11.13.


A distinctive neurobehavioural condition with severe developmental delay, profound speech impairment, an ataxic wide-based gait, and a specific behavioural phenotype (excitable personality, hand-flapping, and inappropriately happy affect). Seizures are common.


The genetics of AS are complex. Refer to a clinical geneticist.


Fragile X syndrome (FRAXA)


·Incidence 71/5500 males. It is the most common inherited cause of mental retardation.


Caused by a full expansion (>200 repeats) in the (CGG)n triplet repeat in the FRAXA gene on chromosome Xq27.3.

Boys with fragile X syndrome typically have global developmental delay often with gaze avoidance, stereotyped repetitive behaviours such as hand-flapping and resistance to change of routines.

Up to 50% of girls with a full FRAXA expansion will have learning and behavioural difficulties that are similar to, but less severe, than those seen in affected boys.

Genetic counselling is very complex and there will be genetic implications for relatives. Referral to a clinical geneticist is recommended.


Prader–Willi syndrome


Rett syndrome


Affects 71/10 000 female births.

Caused by mutation in the MECP2 gene on Xq28. Girls with Rett syndrome appear normal in the first 6 months of life.

A severe neurodevelopmental disorder. Almost exclusively affects girls. Presents after age 1yr usually with developmental regression and loss of purposeful hand movements. May develop seizures, scoliosis, erratic breathing with episodes of breath-holding and hyperventilation, and stereotypic hand-wringing.


Smith–Magenis syndrome


Affects at least 1/25,000 children.


Usually caused by a de novo microdeletion on chromosome 17p11.2.


Typical features include a broad face with midface hypoplasia, brachydactyly, obesity, developmental delay/learning disability with behavioural disturbance, especially of sleep (night-time waking and daytime somnolence).


The diagnosis may be missed on a routine chromosome analysis and may require FISH for the 17p11.2 microdeletion.

Williams syndrome


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