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Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts., Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts., Results: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts., Conclusion: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Purpose: Fabry disease is a pan-ethnic, progressive, X-linked genetic disorder that commonly presents in childhood and is caused by deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A). Symptoms of Fabry disease in the pediatric population are well described for patients over five years of age; however, data are limited for infancy and early childhood. The purpose of this article is to delineate the age of detection for specific Fabry symptoms in early childhood., Methods: A systematic retrospective analysis of PubMed indexed, peer-reviewed publications and case reports in the pediatric Fabry population was performed to review symptoms in patients reported before 5 years of age., Results: The most frequently reported symptom in all age groups under 5 years was acroparesthesias/neuropathic pain, reported in 9 children, ranging in age from 2.0-4.0 years. Also notable is the frequency of gastrointestinal issues reported in 6 children aged 1.0-4.1 years of age., Conclusion: This article finds clear evidence that symptoms can occur in early childhood, before age 5 years. Given early presenting symptoms and the ability to monitor these disease hallmarks, a timely referral to a medical geneticist or other specialty clinician experienced in managing children with Fabry disease is strongly indicated.

Purpose: To investigate the potential influence of additional copy number variants in patients with 15q24 rearrangements and the possible underlying mechanisms for these rearrangements., Methods: Oligonucleotide-based chromosomal microarray analyses were performed, and the results were subsequently confirmed by fluorescence in situ hybridization analyses. Long-range polymerase chain reaction amplification and DNA sequencing analysis were used for breakpoint junction sequencing., Results: We describe a 15-year-old boy with cognitive impairment and dysmorphic features with deletions in 15q24 and 3q21, a 2-month-old female infant with growth deficiency, heterotaxy, cardiovascular malformations, intestinal atresia, and duplications in 15q24 and 16q22, and a 3.5-year-old boy with developmental delay, microcephaly, and dysmorphic features, with duplications in 15q24 and 2q36.3q37.1. Breakpoint sequencing for the 15q24 deletion in the first patient revealed microhomology and suggested the underlying mechanism of either nonhomologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication., Conclusions: The three described patients with 15q24 rearrangements have copy number variants at other loci and exhibit additional clinical features with a more severe phenotype than that observed in previously reported patients with isolated 15q24 rearrangements, suggesting that the genomic mutational load may contribute to the phenotypic severity and variability in patients with 15q24 rearrangements.