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Michot C.,Paris-Sorbonne University | Le Goff C.,Paris-Sorbonne University | Mahaut C.,Paris-Sorbonne University | Afenjar A.,Center de Reference Maladies Rares Anomalies du Developpement | And 28 more authors.
European Journal of Human Genetics | Year: 2014

Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome. © 2014 Macmillan Publishers Limited All rights reserved.

Marttila M.,University of Helsinki | Lehtokari V.-L.,University of Helsinki | Marston S.,Imperial College London | Nyman T.A.,University of Helsinki | And 34 more authors.
Human Mutation | Year: 2014

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding. © 2014 WILEY PERIODICALS, INC.

PubMed | University of Glasgow and West of Scotland Regional Genetics Service
Type: Journal Article | Journal: PloS one | Year: 2016

Previous studies have demonstrated the influence of changes in the age at which women give birth, and of developments in prenatal screening and diagnosis on the number of pregnancies diagnosed and terminated with chromosomal anomalies. However, we are unaware of any population studies examining pregnancy terminations after diagnosis of chromosomal anomalies that has included all aneuploidies and the influence of maternal factors. The aims of this study were to examine the association between results of prenatal tests and pregnancy termination, and the proportion of foetuses with and without chromosomal anomalies referred for invasive diagnostic tests over time. Diagnostic information of 26,261 prenatal invasive tests from all genetic service laboratories in Scotland from 2000 to 2011 was linked to Scottish Morbidity Records to obtain details on pregnancy outcome. Binary logistic regression was carried out to test the associations of year and type of diagnosis with pregnancy termination, while controlling for maternal age, neighbourhood deprivation and parity. There were 24,155 (92.0%) with no chromosomal anomalies, 1,483 (5.6%) aneuploidy diagnoses, and 623 (2.4%) diagnoses of anomaly that was not aneuploidy (including translocations and single chromosome deletions). In comparison with negative test results, pregnancies diagnosed with trisomy were most likely to be terminated (adjusted OR 437.40, 95% CI 348.19-549.46) followed by other aneuploid anomalies (adjusted OR 95.94, 95% CI 69.21-133.01). During the study period, fewer pregnancies that were diagnosed with aneuploidy were terminated, including trisomy diagnoses (adjusted OR 0.44, 95% CI 0.26-0.73). Older women were less likely to terminate (OR 0.35, 95% CI 0.28, 0.42), and parity was also an independent predictor of termination. In keeping with previous findings, while the number of invasive diagnostic tests declined, the proportion of abnormal results increased from 6.09% to 10.88%. Systematic advances in prenatal screening have improved detection rates for aneuploidy. This has been accompanied by a reduction in the rate of termination for aneuploidy. This may reflect societal changes with acceptance of greater diversity, but this is speculation, and further research would be needed to test this.

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