How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with <i>CHAT</i> or <i>SLC18A3</i> mutations lead to congenital myasthenic syndrome

Schwartz, Mathias; Sternberg, Damien; Whalen, Sandra; Afenjar, Alexandra; Isapof, Arnaud; Chabrol, B.; Portnoı̈, Marie-France; Heide, Solveig; Keren, Boris; Chantot‐Bastaraud, Sandra; Siffroi, Jean‐Pierre

doi:10.1002/ajmg.a.38515

Cited by 14 publications

(27 citation statements)

References 22 publications

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“…16 Stankiewicz et al identified 24 patients with common clinical feature development retardation and intellectual disability with 10q11.21-q11.23 deletion. 9 It has been shown that 10q11.21q11.23 region is a recurrent deletion site, although the fracture regions vary. 8 Other cases of a 10q11.2 deletion showed a development delay patient, 17 Additionally, Langley et al reported a patient with hyperactivity disorder.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual

et al. 2020

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The Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by multisystemic malformations. CdLS is due to mutations in one of the following genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. On the other hand, 10q11.2 deletions cause a wide range of presentations in patients. Approximately 40 cases with variable deletions of 10q11.2 have been reported in literature. Some of the reported cases involve the coexistence of duplication or deletion affecting one copy of the chromosome. However, deletion of chromosome 10q11.22-q11.23 and CdLS syndrome caused by NIPBL gene mutations have not been reported previously. This report, therefore, is the first to report their coexistence together.

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Section: Discussionmentioning

confidence: 99%

“…The only clinical feature common to a majority of patients were intellectual disability and developmental delay 9. To date, over 30 cases with variable deletions of 10q11.22-q11.23 have been reported in literature.Chen et al reported a 22-week fetus with a 10q11.21q11.23 (45,946,150--50,945,014) Â 1 deletion.…”

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A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual

et al. 2020

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“…Our group previously developed a mouse model with reduced expression of VAChT (VAChT KD HOM ) and found motor, 10,11 cardiac, 28 and synaptic 4,[8][9][10]12 alterations that resemble some of the features later discovered in CMS patients with mutations in VAChT. 6,7 Interestingly, adult animals already exhibit cognitive and behavioral impairment, with a 40% to 50% decrease in expression level of VAChT, 10 suggesting that central cholinergic synapses are even more sensitive to decreased VAChT activity than peripheral synapses, in which symptoms appear only after a 70% decrease in VAChT expression. 10 However, the possible effects of a long-term reduced ACh release at the neuromuscular junction have not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in this gene were recently identified in patients with different types of CMS (OMIN No. 617239) . Complete loss of function of VAChT disrupts the basis of cholinergic neurotransmission, leading to severe hypotonia and respiratory failure in humans .…”

Section: Introductionmentioning

confidence: 99%

“…617239). 5,6 Complete loss of function of VAChT disrupts the basis of cholinergic neurotransmission, leading to severe hypotonia and respiratory failure in humans. 7 In addition, VAChT knock-out (VAChT del/del ) mice die shortly after birth, indicating that VAChTmediated storage of ACh is essential for life and contributes to the normal development of the NMJ.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the neuromuscular junction in a middle‐aged mouse model of congenital myasthenic syndrome

et al. 2019

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Introduction Reduced expression of the vesicular acetylcholine transporter (VAChT) leads to changes in the distribution and shape of synaptic vesicles (SVs) at neuromuscular junctions (NMJs), suggesting vesicular acetylcholine (ACh) as a key component of synaptic structure and function. It is poorly understood how long‐term changes in cholinergic transmission contribute to age‐ and disease‐related degeneration in the motor system. Methods In this study we performed confocal imaging, electrophysiology, electron microscopy, and analyses of respiratory mechanics of the diaphragm NMJ components in 12‐month‐old wild‐type (WT) and VAChTKDHOM mice. Results Diaphragms of NMJs of the VAChTKDHOM mice were similar to those in WT mice in number, colocalization, and fragmentation of pre−/postsynaptic components. However, they had increased spontaneous SV exocytosis, miniature endplate potential frequency, and diminished MEPP amplitude. No impairment in respiratory mechanics at rest was observed, probably due to the large neurotransmission safety factor of the diaphragm. Discussion The present findings help us to understand the consequences of reduced ACh release at the NMJs during aging.

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SLC18A3 variants lead to fetal akinesia deformation sequence early in pregnancy

Hakonen

Polvi

Saloranta

et al. 2019

American J of Med Genetics Pt A

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Fetal akinesia deformation sequence (FADS) and lethal multiple pterygium syndrome (LMPS) are clinically overlapping syndromes manifesting with reduced or absent fetal movement, arthrogryposis, and several anomalies during fetal life. The etiology of these syndromes is heterogeneous, and in many cases it remains unknown. In order to determine the genetic etiology of FADS in two fetuses with fetal akinesia, arthrogryposis, edema, and partial cleft palate, we utilized exome sequencing. Our investigations revealed a homozygous nonsense variant [c.1116C>A, p.(Cys372Ter)] in the SLC18A3 gene, which encodes for the vesicular acetylcholine transporter (VAChT) responsible for active transport of acetylcholine in the neuromuscular junction. This is the first description of a nonsense variant in the SLC18A3 gene, as only missense variants and whole gene deletions have been previously identified in patients. The previously detected SLC18A3 defects have been associated with congenital myasthenic syndromes, and therefore our findings extend the clinical spectrum of SLC18A3 defects to severe prenatal phenotypes. Our findings suggest that nonsense variants in SLC18A3 cause a more severe phenotype than missense variants and are in line with previous studies showing a lethal phenotype in VAChT knockout mice. Our results underline the importance of including SLC18A3 sequencing in the differential diagnostics of fetuses with arthrogryposis, FADS, or LMPS of unknown etiology.

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How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome

Cited by 14 publications

References 22 publications

A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual

A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual

Evaluation of the neuromuscular junction in a middle‐aged mouse model of congenital myasthenic syndrome

SLC18A3 variants lead to fetal akinesia deformation sequence early in pregnancy

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