Genomic detection of a familial 382 Kb 6q27 deletion in a fetus with isolated severe ventriculomegaly and her affected mother

Abstract

Terminal deletions of the chromosome 6q27 region are rare genomic abnormalities, linked to specific brain malformations and other neurological phenotypes. Reported cases have variable sized genomic deletions that harbor several genes including the DLL1 and TBP. We report on an inherited 0.38 Mb terminal deletion of chromosome 6q27 in a 22-week fetus with isolated bilateral ventriculomegaly and her affected mother using microarray-based comparative genomic hybridization and fluorescent in situ hybridization (FISH). The deleted region harbors at least seven genes including DLL1 and TBP. The affected mother had a history of hydrocephalus, developmental delay, and seizures commonly associated with DLL1 and TBP 6q27 deletions. This deletion is one of the smallest reported isolated 6q27 terminal deletions. Our data provides additional evidence that haploinsufficiency of the DLL1 and TBP genes may be sufficient to cause the ventriculomegaly, seizures, and developmental delays associated with terminal 6q27 deletions, indicating a plausible role in the abnormal development of the central nervous system.

Universal chromosomal microarray analysis reveals high proportion of copy‐number variants in low‐risk pregnancies

“…Overall, the risk for a clinically significant early-onset CNV (P/LP or SL > 10%, not including XLI) in the low-risk group was 1.12%, and 1.06% when including only findings < 10 Mbp. Information on each of the P/LP syndromes is given in Table S1 [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] , and detailed information on each of these pregnancies is given in Table S2. SLs > 10% are given in Table 3 [5][6][7][38][39][40][41] .…”

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series

“…[1][2][3][4]9, Most 6qter deletions are sporadic, however, rare familial cases have been reported. 3,7,11,13,26,29 The phenotype varies widely, even among the affected members of It is noteworthy that the rate of cerebellar hypoplasia, corpus callosum abnormalities, and abnormal cortical gyration are higher in our series compared to the literature (Table 5). This may be due to recent advances in ultrasound analysis of the fetal brain and the improved description of identified anomalies.…”

“…In the prenatal setting, only fourteen fetuses have been reported. 2,[5][6][7][8][9][10][11][12][13][14] Structural brain abnormalities such as ventriculomegaly and cerebellar hypoplasia were the most frequent ultrasound findings reported. In 2018, thanks to a patient with a neurodevelopmental disorder, Thakur et al have narrowed down the critical interval for the brain malformations to a 382 kb region encompassing two candidate genes, DLL1 (Delta-like canonical Notch ligand 1, OMIM#606582) and TBP (TATA box-binding protein, OMIM#600075).…”

“…In 2018, thanks to a patient with a neurodevelopmental disorder, Thakur et al have narrowed down the critical interval for the brain malformations to a 382 kb region encompassing two candidate genes, DLL1 (Delta-like canonical Notch ligand 1, OMIM#606582) and TBP (TATA box-binding protein, OMIM#600075). 13 Recently, patients presenting with developmental delay, intellectual disability, brain anomalies, and harboring heterozygous pathogenic variants in the DLL1 gene have been reported. 15 Interestingly, a comparison of the clinical features of these individuals and those with 6qter deletions demonstrates a nearly complete overlap suggesting that both result from DLL1 haploinsufficiency.…”

“…The deleted segment encompassed five protein-coding genes, namely DLL1 (Delta-like canonical Notch ligand 1, OMIM#606582), TBP (TATA box-binding protein, OMIM#600075), FAM120B (Family with sequence similarity 120B, OMIM#612266), PDCD2 (Programmed cell death 2, OMIM#600866) and PSMB1(Proteasome 20S subunit beta 1, OMIM# 602017). The authors concluded that haploinsufficiency of DLL1 and TBP may be sufficient to cause ventriculomegaly, seizures, and developmental delay 13. More recently, fifteen individuals from twelve unrelated families presenting with a neurodevelopmental disorder and harboring T A B L E 3(Continued)…”