Congenital Hydrocephalus and Hemivertebrae Associated With De NOVO Partial Monosomy 6q (6q25.3→qter)

Li, Y.; Choy, Kwong Wai; Xie, Hong‐Ning; Chen, M.; He, Wenyin; Gong, Yafei; Liu, H.-Y.; Song, Yanqin; Xian, Yexing; Sun, Xiaofang; Chen, Xinjie

doi:10.1515/bjmg-2015-0009

Cited by 12 publications

(17 citation statements)

References 25 publications

(47 reference statements)

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“…20 Combined with the functions of DLL1 and its homologs and the prior report of a de novo nonsense variant in an individual with autism spectrum disorder (ASD), this led us to hypothesize that insufficiency of DLL1 causes a human neurodevelopmental disorder. 19,[21][22][23] We report 15 individuals from 12 unrelated families with DD, ID, ASD, seizures, brain malformations, and other multi-system features with heterozygous pathogenic variants in DLL1 ( Figure 1A). These findings establish DLL1 as disease-associated gene and delineate the DLL1-related phenotypes.…”

Section: Summary Of Clinical Featuresmentioning

confidence: 99%

Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Fischer-Zirnsak

Segebrecht

Schubach

et al. 2019

The American Journal of Human Genetics

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Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.

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Section: Summary Of Clinical Featuresmentioning

confidence: 99%

Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Fischer-Zirnsak

Segebrecht

Schubach

et al. 2019

The American Journal of Human Genetics

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“…Hemivertebrae may be isolated or found in association with coexisting multiple anomalies [2,7]. The exact etiology of hemivertebrae is unclear [7,8], involving both genetic and environmental factors [9]. The incidence of karyotypic abnormalities in fetuses with isolated hemivertebrae is low [2,8,10].…”

Section: Discussionmentioning

confidence: 99%

Twin pregnancy complicated with congenital Hemivertebra: report of two cases and literature review

Wang

et al. 2020

BMC Pregnancy Childbirth

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Background: Hemivertebra deformity, involving one or multiple vertebral bodies, is one of the important causes of congenital scoliosis. Congenital fetal hemivertebrae could be diagnosed by ultrasonography and confirmed by fetal magnetic resonance imaging during pregnancy. However, reports of hemivertebrae in twins during the perinatal period are very rare. Case presentation: We report two cases of congenital fetal hemivertebrae, each affecting one fetus in a dichorionic diamniotic (DCDA) twin pregnancy. We have also conducted a literature review of its prenatal screening, diagnosis, management, and outcomes. These two cases of congenital fetal hemivertebrae in one fetus of a DCDA twin were both initially found by ultrasonography and confirmed by fetal magnetic resonance imaging (MRI). One couple chose selective termination of the hemivertebrae fetus after they were extensively counseled by the multidisciplinary team regarding the treatment and prognosis of the hemivertebrae twin, and a healthy baby weighing 2320 g was delivered at the 37 + 1 gestational week. The other couple decided to continue the twin pregnancy and gave birth to two living newborns weighing 2580 g and 2060 g at 37 + 1 gestational weeks. These three babies were all in good health during follow-up. Conclusions: Based on our center's experience, comprehensive ultrasonography is necessary for early prenatal diagnosis of this condition. In addition, fetal MRI will confirm the diagnosis of hemivertebrae and provide parents with helpful information for their decision about the fate of the affected fetus.

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“…Prenatal diagnosis of microscopic and submicroscopic deletion of chromosome 6q27 in association with VM is extremely rare and to the best of our knowledge only eight such patients have been reported (Le Caignec et al, ; Valduga et al, ; Li et al, ; Wadt et al, ; Conti et al, ; Peddibhotla et al, ; Li et al, ). Of these, only three cases had isolated VM (Li et al, ; Wadt et al, ) while five cases had additional malformations (Le Caignec et al, ; Valduga et al, ; Conti et al, ; Peddibhotla et al, ; Li et al, ). Five of the reported deletions were de novo, and three were inherited from an affected or mildly affected parent (Le Caignec et al, ; Wadt et al, ).…”

Section: Discussionmentioning

confidence: 99%

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

Thakur

Bronshtein

Hankerd

et al. 2018

American J of Med Genetics Pt A

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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.

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Congenital Hydrocephalus and Hemivertebrae Associated With De NOVO Partial Monosomy 6q (6q25.3→qter)

Cited by 12 publications

References 25 publications

Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders

Twin pregnancy complicated with congenital Hemivertebra: report of two cases and literature review

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

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