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Burkitt-Wright E.M.M.,University of Manchester | Bradley L.,Northern Ireland Regional Genetics Service | Shorto J.,University of Manchester | Mcconnell V.P.M.,Northern Ireland Regional Genetics Service | And 9 more authors.
American Journal of Medical Genetics, Part A | Year: 2012

De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. © 2012 Wiley Periodicals, Inc.

Rea G.,Northern Ireland Regional Genetics Service | Stallings R.L.,Royal College of Surgeons in Ireland | Mullarkey M.,Our Ladys Childrens Hospital | Steven McKinstry C.,Royal Victoria Hospital | And 3 more authors.
Clinical Dysmorphology | Year: 2013

A second child of nonconsanguineous parents was born at term by Caesarean section for foetal distress, after a normal pregnancy. Birth weight was 3.4 kg (25th centile). Early developmental milestones were delayed-he sat at 9 months, crawled at 14 months and walked at 20 months. Fine motor development was also delayed. Hearing and vision were normal. Initial assessment by a clinical geneticist was performed at 14 months of age. On examination at that time, occipital-frontal circumference was found to be below the third centile, weight was on the 25th centile and length was on the 50th centile. Dysmorphic features included low set ears, upslanting palpebral fissures with epicanthic folds, a high arched palate and prominent lips (Fig. 1). There was generalized hypotonia, with normal power and reflexes. He had behavioural problems, which included self-injurious behaviour involving biting and head banging. There was a strawberry haemangioma on the abdominal wall. Investigations at that time included comparative genomic hybridization (CGH) (Breen et al., 1999), which identified a de-novo 14q duplication (14q12-q13.1). © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Flanagan J.M.,Childrens University Hospital | Flanagan J.M.,Royal College of Surgeons in Ireland | McMahon G.,Royal College of Surgeons in Ireland | Brendan Chia S.H.,Royal College of Surgeons in Ireland | And 17 more authors.
Heredity | Year: 2010

Classical or transferase-deficient galactosaemia is an inherited metabolic disorder caused by mutation in the human Galactose-1-phosphate uridyl transferase (GALT) gene. Of some 170 causative mutations reported, fewer than 10% are observed in more than one geographic region or ethnic group. To better understand the population history of the common GALT mutations, we have established a haplotyping system for the GALT locus incorporating eight single nucleotide polymorphisms and three short tandem repeat markers. We analysed haplotypes associated with the three most frequent GALT gene mutations, Q188R, K285N and Duarte-2 (D2), and estimated their age. Haplotype diversity, in conjunction with measures of genetic diversity and of linkage disequilibrium, indicated that Q188R and K285N are European mutations. The Q188R mutation arose in central Europe within the last 20 000 years, with its observed east-west cline of increasing relative allele frequency possibly being due to population expansion during the re-colonization of Europe by Homo sapiens in the Mesolithic age. K285N was found to be a younger mutation that originated in Eastern Europe and is probably more geographically restricted as it arose after all major European population expansions. The D2 variant was found to be an ancient mutation that originated before the expansion of Homo sapiens out of Africa. © 2010 Macmillan Publishers Limited. All rights reserved.

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