BackgroundDisorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.ResultsWe analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management.ConclusionsOur massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1105-y) contains supplementary material, which is available to authorized users.

Levels of physical activity declined in boys and girls between the ages 3 and 4-5 yr, whether using objective measures or parental reports of activity.

Stereotypic hand movements are a feature of Rett Syndrome but few studies have observed their nature systematically. Video data in familiar settings were obtained on subjects (n = 144) identified from an Australian population-based database. Hand stereotypies were demonstrated by most subjects (94.4%), 15 categories were observed and midline wringing was seen in approximately 60% of subjects. There was a median of two stereotypies per subject but this number decreased with age. Clapping and mouthing of hands were more prevalent in girls younger than 8 years and wringing was more prevalent in women 19 years or older. Clapping was commoner in those with p.R306C and early truncating mutations, and much rarer in those with p.R106W, p.R270X, p.R168X, and p.R255X. Stereotypies tended to be less frequent in those with more severe mutations. Otherwise, there were no clear relationships between our categories of stereotypies and mutation. Approximately a quarter each had predominantly right and left handed stereotypies and for the remaining half, no clear laterality was seen. Results were similar for all cases and when restricted to those with a pathogenic mutation. Hand stereotypies changed with increasing age but limited relationships with MECP2 mutations were identified.

Study Design. Modified Delphi technique.Objective. To develop guidelines for the clinical management of scoliosis in Rett syndrome through evidence review and consensus expert panel opinion.Summary of Background Data. Rett syndrome is a rare disorder and clinical expertise is thus with small case series. Scoliosis is a frequent association and the evidence base dealing with scoliosis management in this syndrome is limited. Parents of affected girls and women have expressed needs for more information about scoliosis and Rett syndrome.Methods. An initial draft of scoliosis guidelines was created based on literature review and open-ended questions where the literature was lacking. Perspectives of four parents of Rett syndrome patients informed this initial draft. Access to an online and a Microsoft Word formatted version of the draft were then sent to an international, multidisciplinary panel of clinicians via e-mail with input sought using a 2-stage modified Delphi process to reach consensus agreement. Items included clinical monitoring and intervention before the diagnosis of scoliosis; monitoring after the diagnosis of scoliosis; imaging; therapy and conservative management; bracing; and preoperative, surgical, and postoperative considerations.Results. The first draft contained 71 statements, 65 questions. The second draft comprised 88 items with agreement to strong agreement achieved on 85, to form the final guideline document. A comprehensive, life-span approach to the management of scoliosis in Rett syndrome is recommended that takes into account factors such as physical activity, posture, nutritional and bone health needs. Surgery should be considered when the Cobb angle is approximately 40°to 50°and must be supported by specialist management of anesthesia, pain control, seizures, and early mobilization.Conclusion. Evidence-and consensus-based guidelines were successfully created and have the potential to improve care of a complex comorbidity in a rare condition and stimulate research to improve the current limited evidence base.