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Sudden Unexplained Death in Childhood (SUDC) needs to be fully assessed considering its impact on the family, parents and siblings. Inborn Errors of Metabolism (IEM) such as Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) should be taken into consideration when SUDC occurres. Our aim is to present a family with two successive SUDC and to discuss the post-mortem genetics investigations revealing an IEM implication. A complete autopsy with genetic testing was performed when the proband, a 4-year-old girl, died. A few years previously, her older brother had died at the same age and off the same condition. Years later, his exhumation was necessary in order to perform a post-mortem diagnosis.The two siblings were revealed to have had the same pathogenic genotype of the ACADM gene, heterozygous substitutions in ACADM (NM_000016.5): c.985 A>G p.(Lys329Glu) and c.347 G>A p.(Cys116Tyr). In addition, they also both carried a VUS in TECRL , a gene implicated in Catecholaminergic Polymorphic Tachycardia Ventricular (CPVT) and SUDC. We illustrate the importance of exome analyses for investigating unexplained sudden death, especially in children, with the possible impact for genetic counselling in the family. The finding of the implication of ACADM gene in this case, raises likely responsibility of the public health system in countries such as France, who delayed implementation of new born screening for these conditions. Exome analyses in this case detected unexpected complexity in interpretation linked to the identification of a second candidate gene for SUDC. • Genetic sampling and dried blood spot is needed when genetic disease is suspected in front of a young sudden case death. • Metabolic disease, such as MCAD disease, must not be forgotten. • A genetic diagnosis can bring disclosure to the relative of a dead patient, and prevent disease in the siblings. [ABSTRACT FROM AUTHOR]

The objectives of our study were to determine the actual frequency of the different disorders causing neonatal hypotonia and to assess the reliability of the first physical examination as well as the contribution of the main standard diagnostic tests. One hundred and forty-four infants diagnosed with neonatal hypotonia between January 1st 1999 and June 30th 2005 in our tertiary care facility were retrospectively included in the study. Perinatal history, clinical type of hypotonia, results of standard diagnostic tests, final diagnosis and outcome were abstracted from the original charts. A final diagnosis was reached in 120 cases. Central (cerebral) causes represented 82% of the elucidated cases, mostly hypoxic and hemorrhagic lesions of the brain (34%), chromosomal aberrations and syndromic disorders (26%) and brain malformations (12%). Peripheral (neuromuscular) causes were mainly represented by spinal muscular atrophy (6%) and myotonic dystrophy (4%). Positive predictive value of the initial clinical examination was higher in central type hypotonia. Neuroimaging, karyotype analysis and DNA-based tests were the most helpful diagnostic tools. These recent clinical data can be used to improve our strategy in investigating neonatal hypotonia and a diagnostic algorithm is proposed based on our findings. [ABSTRACT FROM AUTHOR]

High-throughput sequencing technologies performed in the clinical setting have the potential to reveal diverse genetic information. Whether it is initially targeted or unsolicited, strictly medical or not, or even information on a carrier status as part of preconception screening, access to genetic information needs to be managed. The aim of the current study was to gather potential attitudes of various stakeholders towards the sharing of genetic information from next-generation sequencing, and more specifically towards incidental findings, predictive findings, non-medical information and carrier status. Answers from a total number of 1631 individuals belonging to four different groups (45 molecular geneticists, 65 genetic counselors, 56 medical advisors to the state insurance plan, and 1465 university students) were collected through online questionnaires. Overall, the study reflects preferences towards the return of health risks related to serious diseases when effective treatment is available and information on reproductive risks. The importance of the perceived medical utility, both for disease prevention and treatment, was the main distinguishing feature. Attitudes from genetic health professionals were found more reluctant to receive a wide range of information. Hands-on experience with the practice of genetic testing is likely to influence perception of the utility of the genetic information that should be delivered. At the same time, perceptions of preconception genetic carrier screening brought out less differences between participants. Better understanding of the underlying interest in genomic information and thorough education on its value and usage are key elements to the adoption of future guidelines and policy that respect bioethical principles. [ABSTRACT FROM AUTHOR]

The phenotype of Bardet-Biedl syndrome (BBS) is defined by the association of retinitis pigmentosa, obesity, polydactyly, hypogenitalism, renal disease and cognitive impairement. The significant genetic heterogeneity of this condition is supported by the identification, to date, of eight genes (BBS1-8) implied with cilia assembly or function. Triallelic inheritance has recently been suggested on the basis of the identification of three mutated alleles in two different genes for the same patient. In a cohort of 27 families, six BBS genes (namely BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8) have been studied. Mutations were identified in 14 families. Two mutations within the same gene have been identified in seven families. BBS1 is most frequently implied with the common M390R substitution at the homozygous state (n=2), or associated with another mutation at BBS1 (n=3). Compound heterozygous mutations have been found in BBS2 (one family) and BBS6 (one family). In seven other families, only one heterozygous mutation has been identified (once in BBS1, twice for BBS2 and three times in BBS6). Although our study did not reveal any families with bona fide mutations in two BBS genes, consistent with a triallelic hypothesis, we have found an excess of heterozygous single mutations. This study underlines the genetic heterogeneity of the BBS and the involvement of possibly unidentified genes.

The Fragile X syndrome is the most common cause of inherited mental retardation. Clinical features are neither specific nor constant and molecular diagnosis is thus widely used since the characterization of the causal mutation in 1991. The aim of this project was to study the evolution of Fragile X diagnosis in France. A preliminary study of the efficiency of screening for the Fragile X mutation in mentally retarded probands with no previous familial diagnosis was done in the Strasbourg's laboratory with a comparison between data from 1991-1994 and 1997-2000. This study showed an improvement in the use of the Fragile X testing regarding the probands' age at diagnosis and the recruitment of sporadic and female cases. To avoid possible bias in clinical referrals and to evaluate the situation nation wide, this study was enlarged to 28 of the 30 laboratories involved in the Fragile X diagnosis in France from 1997 to 2001 (20,816 probands tested, data representative of 95% of the national screening activity). Median age at diagnosis decreased from 9.2 to 5.8 (average 16-11.6y) between the 1991-1994 and the 1997-2001 studies. Over this period, 477 new families were diagnosed with Fragile X, representing 2.8% of tested male probands (417/14,867) and 1.0% of tested female probands (60/5,949). Forty one percent of positive cases corresponded to probands with a familial history of mental retardation, compared to 66% in the initial (1991-1994) study. We also discuss issues concerning premutations discovered in affected individuals and in females with premature ovarian failure (POF).