Whole exome sequencing identifies novel predisposing genes in neural tube defects

Lemay, Philippe; Marco, Patrizia De; Traverso, Monica; Merello, Elisa; Dionne‐Laporte, Alexandre; Spiegelman, Dan; Henrion, Édouard; Diallo, Ousmane; Audibert, François; Michaud, Jacques L.; Cama, Armando; Rouleau, Guy A.; Kibar, Zoha; Capra, Valeria

doi:10.1002/mgg3.467

Cited by 27 publications

(16 citation statements)

References 32 publications

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“…These insights add to our existing knowledge of the genetic mechanisms underlying NTDs development [17]. The ongoing genomic revolution will indeed offer the possibility to carry out genomic projects, with the aim of identifying new variants implicated in the biologic basis of NTDs [16][17][18]. The low rate of NTDs observed in our case series, even more marked than that currently found in HICs [8,[19][20][21], may be explained by some plausible factors: a likely high number of prenatal diagnoses and abortions in our setting, and the phenomenon of health emigration (from Sicily to central-northern Italian regions), that may have contributed to the reduction/underestimation of our cases.…”

Section: Discussionmentioning

confidence: 80%

“…WIPI1, SPHKAP and NCOR1, have recently been associated with anencephaly) [7,16]. These insights add to our existing knowledge of the genetic mechanisms underlying NTDs development [17]. The ongoing genomic revolution will indeed offer the possibility to carry out genomic projects, with the aim of identifying new variants implicated in the biologic basis of NTDs [16][17][18].…”

Section: Discussionmentioning

confidence: 99%

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Neonatal ten-year retrospective study on neural tube defects in a second level University Hospital

et al. 2020

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Background: Aim of this retrospective study was to describe clinical characteristics, diagnostic work-up, management and follow-up of newborns with neural tube defects (NTDs), admitted to the Mother and Child Department of the University Hospital of Palermo, in a ten years period. Methods: The medical records of 7 newborns (5 males and 2 females) admitted, over a 10-year period from January 2010 to March 2020, to our Department on the first day of life were reviewed. Analyzed data were related to familiar and/or maternal risk factors (consanguinity, maternal preexisting and/or gestational diseases, exposure to teratogen/infectious agents, lack of preconception folic acid supplement), demographic (ethnicity/origin, residence) and clinical features (eventual use of assisted reproduction techniques, prenatal diagnosis, gestational age, fetal presentation, type of delivery, birth weight, preoperative imaging, antibiotics and analgesics use, description of the surgery intervention, length of hospital stay, comorbidities, complications), and follow-up. Results: In our sample we observed a wide spectrum of NTDs: 3 newborns had open NTDs, namely myelomeningocele (2 lumbosacral, one of which associated with extradural lipoma, and 1 sacral), and 4 closed ones, including 2 with meningocele (occipital), 1 filar lipoma associated with dermal sinus, and 1 terminal myelocystocele. Our patients were discharged between 8 and 22 days of life. The neurodevelopmental follow-up showed a favorable outcome for 4 of the 7 patients, and the appearance over time of neurological impairment (motor and/or autonomic) in the newborns with open NTDs. Conclusions: This study describes familiar and/or maternal risk factors and demographic and clinical features of a single-center series of newborns with NTDs. It may provide a further outline of the actual phenotypic spectrum of these malformations, and new insights into epidemiological aspects and comprehensive management of the patients, including diagnostic work-up and follow-up evaluations.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Neonatal ten-year retrospective study on neural tube defects in a second level University Hospital

et al. 2020

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“…5,6 Whole exome sequencing (WES) studies on cohorts of patients with NTD have successfully identified genes that contribute or increase the risk of NTD, but have not revealed many monogenic diseases. 7,8 One gene that has been extensively studied in multiple model organisms and has been found to be important in neural tube closure is SHROOM3. Two separate mouse models with loss of function alleles in SHROOM3 have previously been described.…”

Section: Introductionmentioning

confidence: 99%

A homozygous pathogenic variant in SHROOM3 associated with anencephaly and cleft lip and palate

et al. 2020

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Neural tube defects (NTD) are among the most common congenital anomalies, affecting about 1:1000 births. In most cases, the etiology of NTD is multifactorial and the genetic variants associated with them remain largely unknown. There is extensive evidence from animal models over the past two decades implicating SHROOM3 in neural tube formation; however, its exact role in human disease has remained elusive. In this report, we present the first case of a human fetus with a homozygous loss of function variant in SHROOM3. The fetus presents with anencephaly and cleft lip and palate, similar to previously described Shroom3 mouse mutants and is suggestive of a novel monogenic cause of NTD. Our case provides clarification on the contribution of SHROOM3 to human development after decades of model organism research.

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“…The abnormality can be considered as a disorder of neural tube formation, the most common congenital abnormality with varying prevalence dependent upon race and country. Disorders of neural tube formation are related to genetic but also to environmental factors [5,6]. This holds also true for an appendix of the spinal cord.…”

Section: Introductionmentioning

confidence: 93%

Genetic analysis of spinal dysraphism with a hamartomatous growth (appendix) of the spinal cord: a case series

et al. 2020

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Background: Spinal dysraphism with a hamartomatous growth (appendix) of the spinal cord is better known as herniated spinal cord. There are many arguments in favour of considering it a developmental defect. From this point of view, it is a type of neural tube disorder. Neural tube disorders can be caused by multiple factors, including a genetic factor. A common genetic defect in patients with a spinal dysraphism with a hamartomatous growth of the spinal cord is sought for. Case presentation: In two patients with a symptomatic lesion and referred to an academic hospital a genetic analysis was performed after informed consent. Whole-exome analysis was performed. : Whole-exome analysis did not result in identification of a clinically relevant genetic variant.Conclusions: This the first study to investigate the genetic contribution to spinal dysraphism with a hamartomatous growth (appendix) of the spinal cord. We could not establish a genetic cause for this entity. This conclusion cannot be definitive due to the small sample size. However, the incidental occurrence, the lack of reports of inheritance of this disorder and the absence of contribution to syndromal disorders favours a defect of normal development of the spinal cord.

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Whole exome sequencing identifies novel predisposing genes in neural tube defects

Cited by 27 publications

References 32 publications

Neonatal ten-year retrospective study on neural tube defects in a second level University Hospital

Neonatal ten-year retrospective study on neural tube defects in a second level University Hospital

A homozygous pathogenic variant in SHROOM3 associated with anencephaly and cleft lip and palate

Genetic analysis of spinal dysraphism with a hamartomatous growth (appendix) of the spinal cord: a case series

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