Type A competitiveness traits correlate with downregulation of c-Fos expression in patients with type 1 diabetes.

AIM: Type A personality has been associated with increased survival in people with type 1 diabetes (T1D). Systemic low-grade inflammation may play a critical role, as suggested in recent reports, although the links between the inflammatory circulating transcriptome and Type A remain unknown. This prompted our exploration of the potential associations between Type A personality and c-Fos gene expression, a candidate gene closely linked to inflammatory processes, in T1D. METHODS: Type A personality was assessed by Bortner questionnaire in patients with T1D, and two subscales - 'speed' and 'competitiveness' - were used to measure these specific dimensions of Type A. Expression of the c-Fos gene was assessed by a quantitative real-time polymerase chain reaction technique. RESULTS: This pilot study included 20 men with T1D. Multivariable analyses showed an independent inverse association between Type A competitiveness score and c-Fos expression, while a regression model adjusted for age, body mass index and HbA1c levels revealed a significant inverse relationship between c-Fos transcripts and Type A competitiveness (P = 0.003). CONCLUSION: This strong association between Type A competitiveness and reduced c-Fos expression is in line with recent data suggesting a psychobiological influence of the Type A profile in T1D via inflammatory pathways.

CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers.

Intellectual disability (ID), which affects around 2-3% of the general population, is classically divided into syndromic and nonsyndromic forms, with several modes of inheritance. Nonsyndromic autosomal recessive ID (NS-ARID) appears extremely heterogeneous with numerous genes identified to date, including inborn errors of metabolism. The TUSC3 gene encodes a subunit of the endoplasmic reticulum (ER)-bound oligosaccharyltransferase complex, which mediates a key step of N-glycosylation. To date, only five families with NS-ARID and TUSC3 mutations or rearrangements have been reported in the literature. All patients had speech delay, moderate-to-severe ID, and moderate facial dysmorphism. Microcephaly was noted in one third of patients, as was short stature. No patients had congenital malformation except one patient with unilateral cryptorchidism. Glycosylation analyses of patients' fibroblasts showed normal N-glycan synthesis and transfer. We present a review of the 19 patients previously described in the literature and report on a sixth consanguineous family including two affected sibs, with intellectual disability, unspecific dysmorphic features, and no additional malformations identified by high-resolution array-CGH. A homozygous truncating intragenic duplication of the TUSC3 gene leading to an aberrant transcript was detected in two siblings. This observation, which is the first reported case of TUSC3 homozygous duplication, confirms the implication of TUSC3 in NS-ARID and the power of the high-resolution array-CGH in identifying intragenic rearrangements of genes implicated in nonsyndromic ID and rare diseases.

What can we learn from old microdeletion syndromes using array-CGH screening?

Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.