Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion

Tomohiro Ebihara; Taro Nagatomo; Yohei Sugiyama; Tomoko Tsuruoka; Yoshiteru Osone; Masaru Shimura; Makiko Tajika; Keiko Ichimoto; Yuki Naruke; Nana Akiyama; Sze Chern Lim; Yukiko Yatsuka; Kazuhiro R Nitta; Yoshihito Kishita; Takuya Fushimi; Atsuko Okazaki; Akira Ohtake; Yasushi Okazaki; Kei Murayama

doi:10.1016/j.ymgmr.2022.100912

Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion

Mol Genet Metab Rep. 2022 Aug 24:33:100912. doi: 10.1016/j.ymgmr.2022.100912. eCollection 2022 Dec.

Authors

Tomohiro Ebihara¹, Taro Nagatomo², Yohei Sugiyama³, Tomoko Tsuruoka¹, Yoshiteru Osone⁴, Masaru Shimura³, Makiko Tajika³, Keiko Ichimoto³, Yuki Naruke⁵, Nana Akiyama³, Sze Chern Lim⁶, Yukiko Yatsuka⁶, Kazuhiro R Nitta⁶, Yoshihito Kishita^{6

7}, Takuya Fushimi³, Atsuko Okazaki⁶, Akira Ohtake^{8

9}, Yasushi Okazaki^{6

10}, Kei Murayama³

Affiliations

¹ Center for Medical Genetics, Department of Neonatology, Chiba Children's Hospital, Chiba City, Japan.
² Department of Neonatology, Japanese Red Cross Fukuoka Hospital, Fukuoka City, Japan.
³ Center for Medical Genetics, Department of Metabolism, Chiba Children's Hospital, Chiba City, Japan.
⁴ Center for Neonatology, Chiba University Hospital, Chiba City, Japan.
⁵ Department of Pathology, Chiba Children's Hospital, Chiba City, Japan.
⁶ Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University, Graduate School of Medicine, Tokyo, Japan.
⁷ Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan.
⁸ Department of Pediatrics and Clinical Genomics, Saitama Medical University, Moroyama, Saitama, Japan.
⁹ Center for Intractable Diseases, Saitama Medical University Hospital, Moroyama, Saitama, Japan.
¹⁰ Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

Abstract

Biallelic deletions extending into the ATPase family AAA-domain containing protein 3A (ATAD3A) gene lead to infantile lethality with severe pontocerebellar hypoplasia (PCH). However, only 12 such cases have been reported worldwide to date, and the genotype-phenotype correlations are not well understood. We describe cases associated with the same novel biallelic deletions of the ATAD3A and ATAD3B/3A regions in Japanese siblings with severe spinal cord hypoplasia and multiple malformations, including PCH, leading to neonatal death. The ATAD3A protein is essential for normal interaction between mitochondria and endoplasmic reticulum and is important for mitochondrial biosynthesis. The cases were evaluated using whole-genome sequencing for genetic diagnosis of mitochondrial disease. Spinal cord lesions associated with biallelic compound heterozygous deletion extending into the ATAD3A gene have not been reported. In addition, the ATAD3A deletion was 19 base pairs long, which is short compared with those reported previously. This deletion introduced a frameshift, resulting in a premature termination codon, and was expected to be a null allele. The pathological findings of the atrophic spinal cord showed gliosis and tissue destruction of the gray and white matter. We describe spinal cord lesions as a new central nervous system phenotype associated with a biallelic compound heterozygous deletion extending into the ATAD3A gene. Biallelic ATAD3A deletions should be considered in cases of mitochondrial disease with spinal cord hypoplasia and PCH.

Keywords: ATAD3; ATAD3A, ATPase family AAA-domain containing protein 3A; ATAD3B, ATPase family AAA-domain containing protein 3B; ATAD3C, ATPase family AAA-domain containing protein 3C; Apgar, an appearance, score, grimace, activity and respiration; Biallelic deletion; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging; Neonate; PCH, pontocerebellar hypoplasia; PCR, polymerase chain reaction; RARS2, arginyl-tRNA synthetase 2, mitochondrial; SLC25A46, solute carrier family 25 member 46; SNVs, single nucleotide variants; Spinal cord hypoplasia; bp, base pairs; mtDNA, mitochondrial DNA.

Publication types

Case Reports