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There are few well-validated measures that are appropriate for assessing the full range of neurobehavioral presentations in PTEN hamartoma tumor syndrome (PHTS) and other neurodevelopmental genetic syndromes (NDGS). As potential therapeutics are developed, having reliable, valid, free, and easily accessible measures to track a range of neurobehavioral domains will be crucial for future clinical trials. This study focused on the development and initial psychometric evaluation of a set of freely available informant-report survey scales for PHTS-the Neurobehavioral Evaluation Tool (NET). Concept elicitation, quantitative ratings, and cognitive interviewing processes were conducted with stakeholders and clinician-scientist experts, used to identify the most important neurobehavioral domains for this population, and to ensure items were appropriate for the full range of individuals with PHTS. Results of this process identified a PHTS neurobehavioral impact model with 11 domains. The final NET scales assessing these domains were administered to a sample of 384 participants (median completion time = 20.6 min), including 32 people with PHTS, 141 with other NDGS, 47 with idiopathic neurodevelopmental disorder (NDD), and 164 neurotypical controls. Initial psychometric results for the total scores of each scale indicated very good model (ω = 0.83-0.99) and internal consistency reliability (α = 0.82-0.98) as well as excellent test-retest reproducibility at 1-month follow-up (r = 0.78-0.98) and stability at 4-month follow-up (r = 0.76-0.96). Conditional reliability estimates indicated very strong measurement precision in key score ranges for assessing PHTS and other people with NDGS and/or idiopathic NDD. Comparisons across domains between PHTS and the other groups revealed specific patterns of symptoms and functioning, including lower levels of challenging behavior and more developed daily living and executive functioning skills relative to other NDGS. The NET appears to be a reliable and potentially useful tool for clinical characterization and monitoring of neurobehavioral symptoms in PHTS and may also have utility in the assessment of other NDGS and idiopathic NDD. Additional validation work, including convergent and discriminant validity analyses, are needed to replicate and extend these observations., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The importance of gonadal mosaicism in families with apparently de novo mutations is being increasingly recognized. We report on two affected brothers initially suggestive of X-linked or autosomal recessive inheritance. Malan syndrome due to shared NFIX variants was diagnosed in the brothers using exome sequencing. The boys shared the same paternal but not maternal haplotype around NFIX, and deep amplicon sequencing showed ~7% of the variant in paternal sperm but not in paternal blood and saliva. We performed review of previous cases of gonadal mosaicism, which suggests that the phenomenon is not uncommon. Gonadal mosaicism is often not accompanied by somatic mosaicism in tissues routinely used for testing, and if both types of mosaicism are present, the frequency of the variant in sperm is often higher than in somatic cells. In families with shared apparently de novo variants without evidence of parental somatic mosaicism, the transmitting parent may be determined through haplotyping of exome variants. Gonadal mosaicism has important consequences for recurrence risks and should be considered in genetic counseling in families with de novo variants., (© 2019 Wiley Periodicals, Inc.)

19p13.13 microdeletion has been consistently associated with intellectual disability, overgrowth, and macrocephaly. We report a 19p13.13 microdeletion, detected by array CGH, in a girl with moderate intellectual disability, overgrowth with macrocephaly, prominent digit pads and deep digital creases, hypotonia, ataxia, and strabismus. This clinical report helps to delineate the role of some of the deleted genes, as well as the phenotype of recently described 19p13.13 microdeletion syndrome, including the description of novel digital abnormalities., (© 2015 Wiley Periodicals, Inc.)

Patients with microdeletions in the 19p13.2 chromosomal region show developmental delays, overgrowth, and distinctive features with big head appearances. These manifestations are now recognized as Sotos syndrome-like features (Sotos syndrome 2) or Malan syndrome. We identified three female patients with 19p13.2 deletions involving NFIX, a gene responsible for Malan syndrome. We compared the genotypic and phenotypic data of these patients with those of the patients previously reported. The most of the clinical features were found to overlap; however, Chiari malformation type I was observed in two of the three patients evaluated in this study. Because Chiari malformation type I has never been reported in the patients with NSD1-related Sotos syndrome, this finding indicates the possible role of 19p13.2 deletion in patients with mimicking features of Sotos syndrome but have negative NSD1 testing results., (© 2015 Wiley Periodicals, Inc.)