Abstract:

Microcephaly is a prevalent phenotype in patients with neurodevelopmental problems, often with genetic causes. We comprehensively investigated the clinical phenotypes and genetic background of microcephaly in 40 Korean patients. We analyzed their clinical phenotypes and radiologic images and conducted whole exome sequencing (WES) and analysis of copy number variation (CNV). Infantile hypotonia and developmental delay were present in all patients. Thirty-four patients (85%) showed primary microcephaly. The diagnostic yield from the WES and CNV analyses was 47.5%. With WES, we detected pathogenic or likely pathogenic variants that were previously associated with microcephaly in 12 patients (30%); nine of these were de novo variants with autosomal dominant inheritance. Two unrelated patients had mutations in the KMT2A gene. In 10 other patients, we found mutations in the GNB1, GNAO1, TCF4, ASXL1, SMC1A, VPS13B, ACTG1, EP300, and KMT2D genes. Seven patients (17.5%) were diagnosed with pathogenic CNVs. Korean patients with microcephaly show a genetic spectrum that is different from that of patients with microcephaly of other ethnicities. WES along with CNV analysis represents an effective approach for diagnosis of the underlying causes of microcephaly.

Keywords: Korea; chromosomal microarray; low-depth whole genome sequencing; microcephaly; whole exome sequencing (WES).

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Genomic Analysis of Korean Patient With Microcephaly

Supplementary Figure 1

Generation process of a candidate variant list using a four-step strategy.

Click here for additional data file.^{(291K, TIF)}

Supplementary Table 1

List of genes included in silico gene panel for microcephaly.

Click here for additional data file.^{(74K, xlsx)}

Supplementary Table 2

Clinical phenotypes of all patients.

Click here for additional data file.^{(18K, xlsx)}

Supplementary Table 3

List of pathogenic variant, likely pathogenic variant, and variant of uncertain significance with in-silico analysis for microcephaly phenotype genes.

Click here for additional data file.^{(43K, xlsx)}

^{Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea}

^{Department of Laboratory Medicine and Genetics, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, South Korea}

^{Samsung Genome Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea}

^{Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea}

^{Green Cross Genome, Yongin, South Korea}

Edited by: Prashant Kumar Verma, All India Institute of Medical Sciences, Rishikesh, India

Reviewed by: Chiara Di Resta, Vita-Salute San Raffaele University, Italy; ByungChan Lim, Seoul National University Hospital, South Korea

*Correspondence: Jeehun Lee ude.ukks@1010eelhj

This article was submitted to Genetics of Common and Rare Diseases, a section of the journal Frontiers in Genetics

†These authors share first authorship

Edited by: Prashant Kumar Verma, All India Institute of Medical Sciences, Rishikesh, India

Reviewed by: Chiara Di Resta, Vita-Salute San Raffaele University, Italy; ByungChan Lim, Seoul National University Hospital, South Korea

Received 2020 Mar 17; Accepted 2020 Dec 30.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Microcephaly is a prevalent phenotype in patients with neurodevelopmental problems, often with genetic causes. We comprehensively investigated the clinical phenotypes and genetic background of microcephaly in 40 Korean patients. We analyzed their clinical phenotypes and radiologic images and conducted whole exome sequencing (WES) and analysis of copy number variation (CNV). Infantile hypotonia and developmental delay were present in all patients. Thirty-four patients (85%) showed primary microcephaly. The diagnostic yield from the WES and CNV analyses was 47.5%. With WES, we detected pathogenic or likely pathogenic variants that were previously associated with microcephaly in 12 patients (30%); nine of these were de novo variants with autosomal dominant inheritance. Two unrelated patients had mutations in the KMT2A gene. In 10 other patients, we found mutations in the GNB1, GNAO1, TCF4, ASXL1, SMC1A, VPS13B, ACTG1, EP300, and KMT2D genes. Seven patients (17.5%) were diagnosed with pathogenic CNVs. Korean patients with microcephaly show a genetic spectrum that is different from that of patients with microcephaly of other ethnicities. WES along with CNV analysis represents an effective approach for diagnosis of the underlying causes of microcephaly.

Keywords: microcephaly, whole exome sequencing (WES), chromosomal microarray, low-depth whole genome sequencing, Korea

Abstract

Acknowledgments

We are grateful to the patients and their families for their participation in this study and we thank the research coordinator for collecting samples and processing genetic evaluations.

Acknowledgments

Footnotes

Funding. This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2014M3C9A2064619 and NRF-2017R1A2B4005276). The funding body had no role in this study design, data collection, or analysis, decision to publish, or preparation of the manuscript.

Footnotes

Click here for additional data file.^{(291K, TIF)}Click here for additional data file.^{(74K, xlsx)}Click here for additional data file.^{(18K, xlsx)}Click here for additional data file.^{(43K, xlsx)}

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