Combined deletion of two Condensin II system genes (NCAPG2 and MCPH1) in a case of severe microcephaly and mental deficiency

Perche, Olivier; Menuet, Arnaud; Marcos, Mélanie; Liu, Luyan; Pâris, Arnaud; Utami, Kagistia Hana; Kervran, Dominique; Cacheux, Valère; Laudier, Béatrice; Briault, Sylvain

doi:10.1016/j.ejmg.2013.07.007

Cited by 25 publications

(17 citation statements)

References 22 publications

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“…Bijlsma and coworkers sequenced the coding regions of A LDOA , TBX6 and SPN in four patients with 16p11.2 deletion and mild mental retardation. No mutations were found and they concluded that CNVs of 16p11.2 are associated with variable phenotypes [67]. In our study, five MA patients showed the deletion.…”

Section: Discussionsupporting

confidence: 49%

TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia

Sandbacka

Laivuori

Freitas

et al. 2013

Orphanet J Rare Dis

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BackgroundMüllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman’s life. Despite intense research, no major genes have been found to explain the complex genetic etiology.Methods and ResultsWe have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of TBX6, residing within 16p11.2, revealed two patients carrying a splice site mutation. Two previously reported TBX6 variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced LHX1 and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in TBX6 or LHX1 in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in TBX6 or LHX1 in 7/112 (6.3%), and rare variants in TBX6 in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants lending support to the complex genetic etiology of MA.ConclusionsWe have identified TBX6 as a new gene associated with MA. Our results also support the relevance of LHX1 and CNVs in the development of this congenital malformation.

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Section: Discussionsupporting

confidence: 49%

TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia

Sandbacka

Laivuori

Freitas

et al. 2013

Orphanet J Rare Dis

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“…However, heterozygous multi-gene deletions encompassing NCAPG2 on chr7 and MCPH1 on chr8 have been reported in a case of severe microcephaly and intellectual disability. 58 We used GeneMatcher 59 to identify family 2. Independent of, and concurrent with, our TFNG work, trio-based WES was performed in a clinical laboratory.…”

Section: Whole-exome Sequencing Identifies Rare Recessive Mutations Imentioning

confidence: 99%

Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies

Khan

Sadeghpour

et al. 2019

The American Journal of Human Genetics

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The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.We cultured primary dermal fibroblasts in DMEM (Sigma Aldrich), 10% fetal bovine serum (FBS), and 1% penicillin-streptomycin. We synchronized cells by reducing serum content to 0.1% for 24 hr, then by stimulating the cells for 24 hr with 10% FBS. 19

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“…Amniocentesis— The woman is usually also offered an amniocentesis to make a diagnosis of a chromosomal abnormality (such as Down’s syndrome), a specific genetic syndrome (as recommended by a clinical geneticist), and for direct analysis of infectious pathogens if there is a suspicion on maternal serology (such as cytomegalovirus or Toxoplasma ) 252728. Further tests to investigate inborn errors of metabolism are needed if an underlying genetic abnormality is suspected as suggested by a retrospective study 13…”

Section: How Is It Diagnosed?mentioning

confidence: 99%

Fetal microcephaly

Nawathe

Doherty

Pandya

2018

BMJ

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Combined deletion of two Condensin II system genes (NCAPG2 and MCPH1) in a case of severe microcephaly and mental deficiency

Cited by 25 publications

References 22 publications

TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia

TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia

Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies

Fetal microcephaly

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