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

Lesieur-Sebellin, Marion; Till, Marianne; Kien, Philippe Khau Van; Hervé, Bérénice; Bourgon, Nicolas; Dupont, Céline; Tabet, Anne‐Claude; Barrois, M.; Coussement, A.; Lœuillet, Laurence; Mousty, E.; Ea, Vuthy; Assal, Amal; Mary, Laura; Jaillard, Sylvie; Bénéteau, Claire; Vaillant, C. Le; Coutton, Charles; Devillard, Françoise; Goumy, Carole; Delabaere, Amélie; Redon, Sylvia; Laurent, Y.; Massardier, Jérôme; Turleau, C; Sanlaville, Damien; Cantagrel, Vincent; Sonigo, P.; Vialard, François; Salomon, Laurent; Malan, Valérie

doi:10.1002/pd.6074

Cited by 6 publications

(5 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lesieur‐Sebellin et al. presented 22 case series of fetuses diagnosed with a pure 6q deletion 40 . The ultrasound findings showed cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities as the most common (70%), while gyration abnormalities occurred in 46% of patients.…”

Section: Resultsmentioning

confidence: 99%

“…Lesieur-Sebellin et al presented 22 case series of fetuses diagnosed with a pure 6q deletion. 40 The ultrasound findings showed cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities as the most common (70%), while gyration abnormalities occurred in 46% of patients. Cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, or kidney abnormalities were described as rare.…”

Section: Q Terminal Deletionmentioning

confidence: 91%

See 1 more Smart Citation

Epilepsy, EEG and chromosomal rearrangements

Paprocka,

Coppola,

Cuccurullo

et al. 2024

Epilepsia Open

View full text Add to dashboard Cite

Chromosomal abnormalities are associated with a broad spectrum of clinical manifestations, one of the more commonly observed of which is epilepsy. The frequency, severity, and type of epileptic seizures vary according to the macro‐ and microrearrangements present. Even within a single chromosomal anomaly, we most often deal with a phenotypic spectrum. The aim of the study was to look for chromosomal rearrangements with a characteristic electroencephalographic pattern. Only a few disorders have peculiar electroclinical abnormalities: 1p36, 4p16, 6q terminal or trisomy 12p, Angelman syndrome, inv dup 15, 15q13.3 deletions, ring 20, Down syndrome, or Xp11.22–11.23 duplication. We also reviewed studies on epileptic seizures and typical electroencephalographic patterns described in certain chromosomal rearrangements, focusing on the quest for potential electroclinical biomarkers. The comprehensive review concludes with clinical presentations of the most common micro and macro chromosomal rearrangements, such as 17q21.31 microdeletion, 6q terminal deletion, 15q inv dup syndrome, 2q24.4 deletion, Xp11.22–11.23 duplication, 15q13.3 microdeletion, 1p36 terminal deletion, 5q14.3 microdeletion, and Xq28 duplication. The papers reviewed did not identify any specific interictal electroencephalographic patterns that were unique and significant biomarkers for a given chromosomal microrearrangement. The types of seizures described varied, with both generalized and focal seizures of various morphologies being reported. Patients with chromosomal anomalies may also meet the criteria for specific epileptic syndromes such as Infantile Epilepsy Spasms Syndrome (IESS, West syndrome): 16p13.11, 15q13.3 and 17q21.31 microdeletions, 5q inv dup. syndrome; Dravet syndrome (2q24.4 deletion), Lennox–Gastaut syndrome (15q11 duplication. 1q13.3, 5q inv dup.); or Self‐Limited Epilepsy with Autonomic Features (SeLEAS, Panayiotopoulos syndrome: terminal deletion of 6q.n), Self‐Limited Epilepsy with Centrotemporal Spikes (SeLECT): fragile X syndrome. It is essential to better characterize groups of patients to more accurately define patterns of epilepsy and EEG abnormalities. This could lead to new treatment strategies. Future research is required to better understand epileptic syndromes and chromosomal rearrangements.Plain Language SummaryThis paper presents EEG recording abnormalities in patients with various gene abnormalities that can cause epilepsy. The authors summarize these EEG variations based on a literature review to see if they occur frequently enough in other chromosomal abnormalities (in addition to those already known) to be a clue for further diagnosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Q Terminal Deletionmentioning

confidence: 91%

Epilepsy, EEG and chromosomal rearrangements

Paprocka,

Coppola,

Cuccurullo

et al. 2024

Epilepsia Open

View full text Add to dashboard Cite

show abstract

“…As all these clinical characteristics are also seen in our terminal 6q deletion cohorts, it is very likely that haploinsufficiency of DLL1 makes an important contribution to the common terminal 6q deletion phenotype. Lesieur-Sebellin et al characterised the features detected by prenatal ultrasound in 22 foetuses with terminal 6q deletions and pointed out the gene DLL1 as the major contributor to the detected phenotype [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role for DLL1

Engwerda

Kerstjens-Frederikse

Corsten‐Janssen

et al. 2023

Orphanet J Rare Dis

View full text Add to dashboard Cite

Background Terminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the project is to improve the surveillance of patients with chromosome 6 aberrations and the support for their families by increasing the available information about these rare aberrations. This parent-driven research project makes use of information collected directly from parents via a multilingual online questionnaire. Here, we report our findings on 93 individuals with terminal 6q deletions and 11 individuals with interstitial 6q26q27 deletions, a cohort that includes 38 newly identified individuals. Results Using this cohort, we can identify a common terminal 6q deletion phenotype that includes microcephaly, dysplastic outer ears, hypertelorism, vision problems, abnormal eye movements, dental abnormalities, feeding problems, recurrent infections, respiratory problems, spinal cord abnormalities, abnormal vertebrae, scoliosis, joint hypermobility, brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures, hypotonia, ataxia, torticollis, balance problems, developmental delay, sleeping problems and hyperactivity. Other frequently reported clinical characteristics are congenital heart defects, kidney problems, abnormalities of the female genitalia, spina bifida, anal abnormalities, positional foot deformities, hypertonia and self-harming behaviour. The phenotypes were comparable up to a deletion size of 7.1 Mb, and most features could be attributed to the terminally located gene DLL1. Larger deletions that include QKI (> 7.1 Mb) lead to a more severe phenotype that includes additional clinical characteristics. Conclusions Terminal 6q deletions cause a common but highly variable phenotype. Most clinical characteristics can be linked to the smallest terminal 6q deletions that include the gene DLL1 (> 500 kb). Based on our findings, we provide recommendations for clinical follow-up and surveillance of individuals with terminal 6q deletions.

show abstract

“…The key role of DLL1 is supported by cases with brain anomalies, intellectual disability and pathogenic variants in DLL1 gene. DLL1 gene is Notch ligand with an important role in development of the central nervous system (regulates neuronal differentiation), somites and lymphocytes (Striano et al, 2006;Peddibhotla et al, 2015;Fischer-Zirnsak et al, 2019;Hanna et al, 2019;Lesieur-Sebellin et al, 2022).…”

Section: Autosomal Recessivementioning

confidence: 99%

Genetic heterogeneity in corpus callosum agenesis

et al. 2022

View full text Add to dashboard Cite

The corpus callosum is the largest white matter structure connecting the two cerebral hemispheres. Agenesis of the corpus callosum (ACC), complete or partial, is one of the most common cerebral malformations in humans with a reported incidence ranging between 1.8 per 10,000 livebirths to 230–600 per 10,000 in children and its presence is associated with neurodevelopmental disability. ACC may occur as an isolated anomaly or as a component of a complex disorder, caused by genetic changes, teratogenic exposures or vascular factors. Genetic causes are complex and include complete or partial chromosomal anomalies, autosomal dominant, autosomal recessive or X-linked monogenic disorders, which can be either de novo or inherited. The extreme genetic heterogeneity, illustrated by the large number of syndromes associated with ACC, highlight the underlying complexity of corpus callosum development. ACC is associated with a wide spectrum of clinical manifestations ranging from asymptomatic to neonatal death. The most common features are epilepsy, motor impairment and intellectual disability. The understanding of the genetic heterogeneity of ACC may be essential for the diagnosis, developing early intervention strategies, and informed family planning. This review summarizes our current understanding of the genetic heterogeneity in ACC and discusses latest discoveries.

show abstract

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

Cited by 6 publications

References 69 publications

Epilepsy, EEG and chromosomal rearrangements

Epilepsy, EEG and chromosomal rearrangements

The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role for DLL1

Genetic heterogeneity in corpus callosum agenesis

Contact Info

Product

Resources

About