Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome

The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5′UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated

Supplementary Material for: Noninvasive Prenatal Detection of Trisomy 21 by Targeted Semiconductor Sequencing: A Technical Feasibility Study

<p><b><i>Objective:</i></b> To develop an alternate noninvasive prenatal testing method for the assessment of trisomy 21 (T21) using a targeted semiconductor sequencing approach. <b><i>Methods:</i></b> A customized AmpliSeq panel was designed with 1,067 primer pairs targeting specific regions on chromosomes 21, 18, 13, and others. A total of 235 samples, including 30 affected with T21, were sequenced with an Ion Torrent Proton sequencer, and a method was developed for assessing the probability of fetal aneuploidy via derivation of a risk score. <b><i>Results:</i></b> Application of the derived risk score yields a bimodal distribution, with the affected samples clustering near 1.0 and the unaffected near 0. For a risk score cutoff of 0.345, above which all would be considered at “high risk,” all 30 T21-positive pregnancies were correctly predicted to be affected, and 199 of the 205 non-T21 samples were correctly predicted. The average hands-on time spent on library preparation and sequencing was 19 h in total, and the average number of reads of sequence obtained was 3.75 million per sample. <b><i>Conclusion:</i></b> With the described targeted sequencing approach on the semiconductor platform using a custom-designed library and a probabilistic statistical approach, we have demonstrated the feasibility of an alternate method of assessment for fetal T21.</p

Co-ordinating meaning within a gender identity development service: What can the theory of the co-ordinated management of meaning offer clinicians working with young people, and their families, exploring their gender identities

Working with young people who present with diverse gender identifications and their families requires consideration and acknowledgement of a range of contexts (including relationship, family, social and cultural) as well as the influences of prior experience and language. Family members often present with diverse understandings and hopes from their referral to the Gender Identity Development Service and look to us to meet these. This article considers the contribution of Cronen and Pearce who introduced the theory of the co-ordinated management of meaning (CMM). We focus on their ideas about communication, the complexities of communication, meaning, context and multiple perspectives. This article relates to our practice as well as considers useful ways to work with families and young people, within a highly contested field. Clinical examples are used to illustrate how we have made use of the theory and models of CMM to facilitate engagement, build therapeutic rapport, facilitate understanding and support those we see in a way which takes into account the many contexts of their lives