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Mosaic parental germline mutations causing recurrent forms of malformations of cortical development.

ABSTRACT: To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.

SUBMITTER: Zillhardt JL

PROVIDER: S-EPMC4929884 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Mosaic parental germline mutations causing recurrent forms of malformations of cortical development.

Zillhardt Julia Lauer JL Poirier Karine K Broix Loïc L Lebrun Nicolas N Elmorjani Adrienne A Martinovic Jelena J Saillour Yoann Y Muraca Giuseppe G Nectoux Juliette J Bessieres Bettina B Fallet-Bianco Catherine C Lyonnet Stanislas S Dulac Olivier O Odent Sylvie S Rejeb Imen I Ben Jemaa Lamia L Rivier Francois F Pinson Lucile L Geneviève David D Musizzano Yuri Y Bigi Nicole N Leboucq Nicolas N Giuliano Fabienne F Philip Nicole N Vilain Catheline C Van Bogaert Patrick P Maurey Hélène H Beldjord Cherif C Artiguenave François F Boland Anne A Olaso Robert R Masson Cécile C Nitschké Patrick P Deleuze Jean-François JF Bahi-Buisson Nadia N Chelly Jamel J

European journal of human genetics : EJHG 20150923 4

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be ...[more]

PMID: 26395554

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Project description:BackgroundThe most common subtypes of malformations of cortical development (MCDs) are gray matter heterotopia (GMH), focal cortical dysplasia (FCD), and polymicrogyria (PMG). This study aimed to characterize the possible neurometabolic abnormalities and heterogeneity in different MCDs subtypes using proton magnetic resonance spectroscopy (1H-MRS).MethodsIn this prospective cross-sectional study, we recruited 29 patients with MCDs and epilepsy, including ten with GMH, ten with FCD, and nine with PMG, as well as 25 age- and sex-matched healthy controls (HC) from the Epilepsy Center of West China Hospital of Sichuan University between August 2018 and November 2021. Inclusion criteria for the patients were based upon typical magnetic resonance imaging (MRI) findings of MCDs and full clinical assessment for epilepsy. Single-voxel point-resolved spectroscopy was used to acquire data from both the lesion and the normal-appearing contralateral side (NACS) in patients and from the frontal lobe in HC. Metabolite measures, including N-acetyl aspartate (NAA), myoinositol (Ins), choline (Cho), creatine (Cr), and glutamate + glutamine (Glx) concentrations, were quantitatively estimated with linear combination model (LCModel) software and corrected for the partial volume effect of cerebrospinal fluid (CSF).ResultsThe NAA concentration was lower and the Ins concentration was higher in the MCDs lesions than in the NACS and in HC (P=0.002-0.007), and the Cho and Cr concentrations were higher in MCDs lesions than in HC (P=0.001-0.016). Moreover, the Cho concentration was higher in NACS than in HC (P=0.015). In the GMH lesions, the only metabolic alteration was an NAA reduction (GMH_lesion vs. HC: P=0.001). In the FCD lesions, there were more metabolite abnormalities than in the other two subtypes, particularly a lower NAA and a higher Ins than in HC and NACS (P=0.012-0.042). In the PMG lesions, Cr (lesion vs. HC or NACS: P=0.017-0.021) and Glx (lesion vs. NACS: P=0.043) were increased, while NAA was normal. Correlation analysis revealed that the Cr concentration in MCDs lesions was positively correlated with seizure frequency (r=0.411; P=0.027).ConclusionsBased upon 1H-MRS, our study demonstrated that different MCDs subtypes exhibited variable metabolic features, which may be associated with distinct functional and cytoarchitectural properties.

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Mosaic parental germline mutations causing recurrent forms of malformations of cortical development.

Publications

Mosaic parental germline mutations causing recurrent forms of malformations of cortical development.

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