Explore the vast range of titles available.

Jacquemin et al discuss the possible role of a multidrug resistance 3 (MDR3) gene defect in the pathogenesis of intrahepatic cholestasis of pregnancy.

Bilateral periventricular nodular heterotopia (BPNH) is the most common form of periventricular heterotopia. Mutations in FLNA, encoding filamin A, are responsible for the X linked dominant form of BPNH (FLNA-BPNH). Recently, atypical phenotypes including BPNH with Ehlers–Danlos syndrome (BPNH-EDS) have been recognised. A total of 44 FLNA mutations have so far been reported in this phenotype. Most of these mutations lead to a truncated protein, but few missense mutations have also been described. Here, the results of a mutation screening conducted in a series of 32 BPNH patients with the identification of 12 novel point mutations in 15 patients are reported. Nine mutations were truncating, while three were missense. Three additional patients with BPNH-EDS and a mutation in FLNA are described. No phenotype–genotype correlations could be established, but these clinical data sustain the importance of cardiovascular monitoring in FLNA-BPNH patients.

Background With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers. Methods A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement) , a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed. Results The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID. Conclusion This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES. Trial registration ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.

Genetic link to obesity Obesity is a highly heritable disorder but the genetic associations reported to date account for only a small percentage of the inherited variation in body mass index. Two groups report deletions on chromosome16p11.2 that may explain part of the 'missing heritability' in terms of 'high-penetrance' mutations that are rare but when present are very often associated with severe obesity. This is in contrast to more common gene defects that are less closely associated with clinical symptoms. Bochukova et al . identified rare recurrent copy number variants in 300 patients with severe early-onset obesity, caused by deletions involving several genes including SH2B1 , known to be involved in leptin and insulin signalling. Many of the patients also suffered neurodevelopmental disorders. Walters et al . identified deletions of at least 593 kilobases on chromosome 16p11.2 in 31 patients with a previously unrecognized type of extreme obesity. The strategy they used to identify the lesion — using small well-phenotyped cohorts of extreme phenotypes with targeted follow-up in genome-wide association studies and population cohorts — shows promise as a means of identifying 'missing heritability' in complex metabolic diseases more generally. Recently, numerous single nucleotide polymorphisms have been identified as being associated with obesity, but these loci together account for only a small fraction of the known heritable component. Here, an association is reported between rare deletions of at least 593 kilobases at 16p11.2 and a highly penetrant form of obesity. The strategy used of combining study of extreme phenotypes with targeted follow-up is promising for identifying missing heritability in obesity. Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western ‘obesogenic’ environment and a strong genetic contribution 1 . Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component 1 . Thus, the ‘common disease, common variant’ hypothesis is increasingly coming under challenge 2 . Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) ≥ 40 kg m -2 or BMI standard deviation score ≥ 4; P = 6.4 × 10 -8 , odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3 ). The most productive approach may therefore be to combine the ‘power of the extreme’ 4 in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1 . In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group ( P <0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

Objectives Silver–Russell syndrome (SRS) is an imprinted disorder characterised by intrauterine growth retardation, relative macrocephaly, failure to thrive, typical facial phenotype and frequent body asymmetry. Feeding difficulties are frequently noted, but no study described evolution of gastrointestinal signs during infancy and their management in SRS. The aim of this study was to describe these abnormalities in a large cohort of children with SRS. Design We included 75 patients (median age 24.3 months (5.1–135.2)) in the study. We retrospectively analysed nutritional status before growth hormone therapy, the frequency of gastrointestinal signs, such as gastroesophageal reflux (GER), vomiting, constipation and feeding difficulties, and nutritional management. Results Maternal uniparental disomy for chromosome 7 was found in 10 patients and 11p15 hypomethylation in 65 patients. Malnutrition (defined as a weight/expected weight for height ratio <80%) was detected in 70% of the children. Gastrointestinal signs were found in 77%, including severe vomiting before the age of 1 year in 50% of cases, persistent vomiting from the age of 1 year in 29% of cases and constipation in 20% of cases. Severe GER was diagnosed in 55% of children by 24 h oesophageal pH-metry. Feeding difficulties were described in 65% of cases, with indications for dietary enrichment in 49%. Enteral nutrition by gastrostomy was indicated in 22% of cases. Conclusions Digestive signs (GER, constipation) and malnutrition are frequent in children with SRS. The systematic exploration and management of these signs are crucial to improve the nutritional status of these children before initiating growth hormone therapy.

Dyggve-Melchior-Clausen syndrome (DMC) is an autosomal recessive condition characterised by short trunk dwarfism, scoliosis, microcephaly, coarse facies, mental retardation, and characteristic radiological features. X rays show platyspondyly with double vertebral hump, epiphyseal dysplasia, irregular metaphyses, and a characteristic lacy appearance of the iliac crests. Electron microscopy of chondrocytes have shown widened cisternae of rough endoplasmic reticulum and biochemical analyses have shown accumulation of glucosaminoglycan in cartilage, but the pathogenesis of DMC remains unexplained. Here, we report on the homozygosity mapping of a DMC gene to chromosome 18q21.1 in seven inbred families (Zmax=9.65 at θ=0 at locus D18S1126) in the genetic interval (1.8 cM) defined by loci D18S455 and D18S363. Despite the various geographical origins of the families reported here (Morocco, Tunisia, Portugal, and Lebanon), this condition was genetically homogeneous in our series. Continuing studies will hopefully lead to the identification of the disease causing gene.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 families affected by severe hypophosphatasia. Fourteen distinct mutations were found, 3 of which were previously reported in the North American or Japanese populations. Seven of the 11 new mutations were missense mutations (M45L, R119H, G145V, C184Y and H154Y, D289V, E459K), the four others were 2 single nucleotide deletions (544delG and 1172delC), a mutation affecting donor splice site (862 + 5A) and a nonsense mutation (R411X).

CDMP-1 has been detected in the rat dental pulp, and could intervene in tooth development and maintenance. 8 Heterozygous mutations in CDMP-1 occur in individuals with autosomal dominant BDC. 6 We report on ASPED in a family with three affected members. Since types of ASP distinct from those observed in ASPED have been reported in BDC, 9 and since short first metacarpal and hip dysplasia are common in both ASPED and BDC, we performed molecular biological testing and identified a known CDPM-1 mutation. In the present study, ASPED was identified in three patients from one family (one adult and three children), and clinical and radiological observations evolving with age are reported. Since radiological findings resembling ASPs had been reported in BDC, molecular analysis of the CDMP-1 gene was performed and one causative mutation was identified in this family.