Genetic counseling for women with 45,X/46,XX mosaicism: Towards more personalized management.

Despite numerous clinical series, consistent karyotype-phenotype correlations for Turner syndrome have not been established, although a lower level of 45,X is generally thought to be associated with a milder phenotype. This limits personalized counseling for women with 45,X/46,XX mosaicism. To better understand the phenotypic spectrum associated with various levels of 45,X/46,XX mosaicism, we compared patients evaluated in the Massachusetts General Hospital Turner Syndrome Clinic to determine if cardiac, renal, and thyroid abnormalities correlated with the percentage of 45,X cells present in a peripheral blood karyotype. of the 118 patients included in the study, 78 (66%) patients had non-mosaic 45,X and 40 (34%) patients had varying levels of 45,X/46,XX mosaicism. Patients with ≤70% 45,X compared with those with >70% 45,X had a significantly lower frequency of cardiac and renal anomalies. The presence of hypothyroidism was somewhat lower for the ≤70% 45,X group, but was not statistically significant. Supplemental tissue testing on another tissue type, typically buccal mucosa, was often useful in counseling patients with 45,X mosaicism. Given the modest sample size of patients with varying levels of mosaicism and the variability of Turner syndrome abnormalities, we hope this preliminary study will inspire a multicenter collaboration, which may lead to modification of clinical guidelines. Because several patients with ≤70% 45,X were ascertained from perinatal care referrals, we still advise women with 45,X mosaicism pursuing pregnancy to receive standard Turner syndrome cardiac surveillance. There is an opportunity to personalize counseling and surveillance for patients based on percentage of 45,X cells on chromosome analysis.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years.

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.

Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation.

RASA1-related disorders are vascular malformation syndromes characterized by hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM), arteriovenous fistulas (AVF), or Parkes Weber syndrome. The number of cases reported is relatively small; and while the main clinical features are CMs and AVMs/AVFs, the broader phenotypic spectrum caused by variants in the RASA1 gene is still being defined. Here, we report the clinical and molecular findings in 69 unrelated cases with a RASA1 variant identified at ARUP Laboratories. Sanger sequencing and multiplex ligation-dependent probe amplification were primarily used to evaluate RASA1. Several atypical cases were evaluated using next-generation sequencing (NGS) and array-comparative genomic hybridization (aCGH). Sixty individuals had a deleterious RASA1 variant of which 29 were novel. Nine individuals had a variant of uncertain significance. Five large RASA1 deletions were detected, giving an overall deletion/duplication rate of 8.3% (5/60) among positive cases. Most (75.4%) individuals with a RASA1 variant had CMs, and 44.9% had an AVM/AVF. Clinical findings in several cases expand the RASA1 phenotype. Our data suggest that screening for large RASA1 deletions and duplications in this disorder is important and suggest that NGS multi-gene panel testing is beneficial for the molecular diagnosis of cases with complex vascular phenotypes.