CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Partial tetrasomy 11q resulting from an intrachromosomal triplication of a 22 Mb region of chromosome 11.

Intrachromosomal triplications are complex chromosomal rearrangements which arise during meiosis or mitosis and lead to a tetrasomic dose of the affected genomic regions. We describe a female patient harboring an intrachromosomal triplication who presented to the Genetics clinic with dysmorphic features, including telecanthus, flat facial profile, and prognathism, short stature, widely spaced nipples, multiple allergy complaints, loose bowel movements, and mild speech delay. Microarray analysis showed a copy number gain of a 22.37 Mb region of chromosome 11 between bands 11q14.1 and 11q22.1. This region contains 95 genes and seven microRNAs, none of which have been implicated in a disease resulting from increased gene dosage. FISH analysis using a probe targeted to the middle of the segment of the copy number gain yielded a pattern indicative of a tetrasomy via an intrachromosomal triplication, with three signals on the long arm of one homologue of chromosome 11 and the fourth on the other homologue. Subsequent FISH analysis showed that the middle triplicated fragment was positioned in an inverted orientation relative to the outer fragments. To investigate the mechanism by which the intrachromosomal triplication occurred, SNP microarray analysis was performed. These results were consistent with the presence of multiple haplotypes in the tetrasomic region and suggest that the intrachromosomal triplication in our patient arose in one parent during meiosis. © 2017 Wiley Periodicals, Inc.

A case of constitutional trisomy 3 mosaicism in a teenage patient with mild phenotype.

Constitutional mosaicism for trisomy 3 is extremely rare, with only a few postnatally diagnosed cases reported in the literature. We report a case of constitutional trisomy 3 mosaicism in a 16-year-old female, who presented with chronic joint pain, easy bruising, joint hypermobility and dysmorphic features, including long, thin facies, over-folded dysplastic ears, and Pierre-Robin sequence (PRS) with cleft palate. The patient was small at birth, had cleft palate repair, developed chronic joint pain at age 12, and has a history of mild leukopenia and mild thrombocytopenia. Microarray analysis was consistent with a mosaic gain of an entire chromosome 3. FISH analysis of peripheral blood and buccal cells showed the presence of the supernumerary chromosome 3 in a low percentage of cells in both tissues, suggesting that the nondisjunction event occurred prior to the germ cell layer differentiation. Since trisomy 3 has been observed somatically in lymphoma, a Hematology/Oncology consultation was provided for the patient. The oncologist's evaluation for malignancy was unremarkable. A review of findings from other trisomy 3 patients reported in the literature reveals a diverse phenotypic spectrum and does not show a correlation between the proportion of abnormal cells observed in peripheral blood and the patients' clinical features or severity. This case demonstrates that the clinical presentation of an individual with trisomy 3 is highly individualized and the clinical course is difficult to predict.

De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype.

The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.