Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities

Simo Li; Sanami Takada; Ghada M H Abdel-Salam; Mohamed S Abdel-Hamid; Maha S Zaki; Mahmoud Y Issa; Aida M S Salem; Eriko Koshimizu; Atsushi Fujita; Ryoko Fukai; Toshio Ohshima; Naomichi Matsumoto; Noriko Miyake

doi:10.1038/s41525-024-00437-5

Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities

NPJ Genom Med. 2024 Nov 5;9(1):55. doi: 10.1038/s41525-024-00437-5.

Authors

Simo Li^#¹, Sanami Takada^#², Ghada M H Abdel-Salam³, Mohamed S Abdel-Hamid⁴, Maha S Zaki³, Mahmoud Y Issa³, Aida M S Salem⁵, Eriko Koshimizu⁶, Atsushi Fujita⁶, Ryoko Fukai^{7

8}, Toshio Ohshima⁹, Naomichi Matsumoto¹⁰, Noriko Miyake^{11

12}

Affiliations

¹ Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
² Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.
³ Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
⁴ Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
⁵ Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.
⁶ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁷ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁸ Medical Science Services, IQVIA Services Japan G.K., Tokyo, Japan.
⁹ Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan. [email protected].
¹⁰ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. [email protected].
¹¹ Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan. [email protected].
¹² Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. [email protected].

^# Contributed equally.

PMID: 39500882
DOI: 10.1038/s41525-024-00437-5

Abstract

We identified two homozygous truncating variants in GON4L [NM_001282860.2:c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in two unrelated families who presented prenatal-onset growth impairment, microcephaly, characteristic face, situs inversus, and developmental delay. The frameshift variant is predicted to invoke nonsense-mediated mRNA decay of all five known GON4L isoforms resulting in the complete loss of GON4L function. The splice site variant located at a region specific to the longer isoforms; therefore, defects of long GON4L isoforms may explain the phenotypes observed in the three patients. Knockdown of Gon4l in rat PC12 cells suppressed neurite outgrowth in vitro. gon4lb knockdown and knockout zebrafish successfully recapitulated the patients' phenotypes including craniofacial abnormalities. We also observed situs inversus in gon4lb-knockout zebrafish embryo. To our knowledge, the relationship between craniofacial abnormalities or situs inversus and gon4lb has not been reported before. Thus, our data provide evidence that GON4L is involved in craniofacial and left-right patterning during development.

Abstract

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