Whole-Genome Sequencing Reveals a Novel Pathogenic GRIN2B Variant in a Patient with Neurodevelopmental Disorder and an inv(6)(p24p11.2)pat.

Autor:	Córdova-Fletes C; Laboratorio de Citogenómica y Microarreglos, Departamento de Bioquímica, Facultad de Medicina, Universidad Autonoma de Nuevo León, Monterrey, Mexico.; Department of Obstetrics and Gynecology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA., Rivera H; Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico., Domínguez-Quezada MG; Laboratorio de Citogenética, División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico., Aguayo-Orozco TA; Laboratorio de Citogenética, División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico., Garza-González E; Laboratorio de Citogenómica y Microarreglos, Departamento de Bioquímica, Facultad de Medicina, Universidad Autonoma de Nuevo León, Monterrey, Mexico., Núñez-García LA; Laboratorio de Citogenómica y Microarreglos, Departamento de Bioquímica, Facultad de Medicina, Universidad Autonoma de Nuevo León, Monterrey, Mexico., Mercado-Silvae FM; Hospital de Pediatría, Unidad Médica de Alta Especialidad, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico., Rosales-Reynoso MA; División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico., Barros-Núñez P; Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico.
Jazyk:	angličtina
Zdroj:	Cytogenetic and genome research [Cytogenet Genome Res] 2024; Vol. 164 (2), pp. 92-102. Date of Electronic Publication: 2024 Jun 22.
DOI:	10.1159/000539975
Abstrakt:	Introduction: Neurodevelopmental disorders (NDDs) are diverse and can be explained by either genomic aberrations or single nucleotide variants. Most likely due to methodological approaches and/or disadvantages, the concurrence of both genetic events in a single patient has hardly been reported and even more rarely the pathogenic variant has been regarded as the cause of the phenotype when a chromosomal alteration is initially identified. Case Presentation: Here, we describe a NDD patient with a 6p nonpathogenic paracentric inversion paternally transmitted and a de novo pathogenic variant in the GRIN2B gene. Molecular-cytogenetic studies characterized the familial 6p inversion and revealed a paternal 9q inversion not transmitted to the patient. Subsequent whole-genome sequencing in the patient-father dyad corroborated the previous findings, discarded inversions-related cryptic genomic rearrangements as causative of the patient's phenotype, and unveiled a novel heterozygous GRIN2B variant (p.(Ser570Pro)) only in the proband. In addition, Sanger sequencing ruled out such a variant in her mother and thereby confirmed its de novo origin. Due to predicted disturbances in the local secondary structure, this variant may alter the ion channel function of the M1 transmembrane domain. Other pathogenic variants in GRIN2B have been related to the autosomal dominant neurodevelopmental disorder MRD6 (intellectual developmental disorder, autosomal dominant 6, with or without seizures), which presents with a high variability ranging from mild intellectual disability (ID) without seizures to a more severe encephalopathy. In comparison, our patient's clinical manifestations include, among others, mild ID and brain anomalies previously documented in subjects with MRD6. Conclusion: Occasionally, gross chromosomal abnormalities can be coincidental findings rather than a prime cause of a clinical phenotype (even though they appear to be the causal agent). In brief, this case underscores the importance of comprehensive genomic analysis in unraveling the wide-ranging genetic causes of NDDs and may bring new insights into the MRD6 variability. (© 2024 S. Karger AG, Basel.)
Databáze:	MEDLINE
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