De novo heterozygous variants in KIF5B cause kyphomelic dysplasia

Toshiyuki Itai¹, Zheng Wang², Gen Nishimura³, Hirofumi Ohashi⁴, Long Guo², Yasuhiro Wakano⁵, Takahiro Sugiura⁵, Hiromi Hayakawa⁶, Mayumi Okada⁷, Takashi Saisu⁸, Ayana Kitta⁹, Hiroshi Doi¹⁰, Kenji Kurosawa¹¹, Yoshihiro Hotta¹², Katsuhiro Hosono¹², Miho Sato¹², Kenji Shimizu¹³, Kazuharu Takikawa¹⁴, Seiji Watanabe¹⁵, Naho Ikeda¹⁶, Mitsuyoshi Suzuki¹⁷, Atsushi Fujita¹, Yuri Uchiyama^{1

18}, Naomi Tsuchida^{1

18}, Satoko Miyatake^{1

19}, Noriko Miyake²⁰, Naomichi Matsumoto¹, Shiro Ikegawa²

Affiliations

¹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
² Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
³ Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan.
⁴ Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
⁵ Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Japan.
⁶ Department of Obstetrics, Aichi Children's Health and Medical Center, Obu, Japan.
⁷ Department of Obstetrics and Gynecology, Genome Medical Center, Toyohashi Municipal Hospital, Toyohashi, Japan.
⁸ Department of Pediatric Orthopaedics, Chiba Child & Adult Orthopaedic Clinic, Chiba, Japan.
⁹ Department of Orthopedic Surgery, Tokyo Women's Medical University, Yachiyo Medical Center, Chiba, Japan.
¹⁰ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
¹¹ Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
¹² Department of Ophthalmology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
¹³ Division of Clinical Genetics and Cytogenetics, Shizuoka Children's Hospital, Shizuoka, Japan.
¹⁴ Department of Pediatric Orthopedics, Shizuoka Children's Hospital, Shizuoka, Japan.
¹⁵ Department of Pediatrics, Izu Medical and Welfare Center, Izunokuni, Japan.
¹⁶ Department of Neonatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan.
¹⁷ Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
¹⁸ Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan.
¹⁹ Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan.
²⁰ Departmentof Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

PMID: 35342932
DOI: 10.1111/cge.14133

De novo heterozygous variants in KIF5B cause kyphomelic dysplasia

Toshiyuki Itai et al. Clin Genet. 2022 Jul.

. 2022 Jul;102(1):3-11.

doi: 10.1111/cge.14133. Epub 2022 Apr 5.

Authors

Affiliations

¹ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
² Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
³ Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan.
⁴ Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
⁵ Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Japan.
⁶ Department of Obstetrics, Aichi Children's Health and Medical Center, Obu, Japan.
⁷ Department of Obstetrics and Gynecology, Genome Medical Center, Toyohashi Municipal Hospital, Toyohashi, Japan.
⁸ Department of Pediatric Orthopaedics, Chiba Child & Adult Orthopaedic Clinic, Chiba, Japan.
⁹ Department of Orthopedic Surgery, Tokyo Women's Medical University, Yachiyo Medical Center, Chiba, Japan.
¹⁰ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
¹¹ Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
¹² Department of Ophthalmology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
¹³ Division of Clinical Genetics and Cytogenetics, Shizuoka Children's Hospital, Shizuoka, Japan.
¹⁴ Department of Pediatric Orthopedics, Shizuoka Children's Hospital, Shizuoka, Japan.
¹⁵ Department of Pediatrics, Izu Medical and Welfare Center, Izunokuni, Japan.
¹⁶ Department of Neonatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan.
¹⁷ Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
¹⁸ Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan.
¹⁹ Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan.
²⁰ Departmentof Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

PMID: 35342932
DOI: 10.1111/cge.14133

Abstract

Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

Keywords: KIF5B; de novo variant; kyphomelic dysplasia; skeletal dysplasia.

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References

REFERENCES

1. Mortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A. 2019;179(12):2393-2419.
1. Hirokawa N, Noda Y. Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol Rev. 2008;88(3):1089-1118.
1. Kalantari S, Filges I. 'Kinesinopathies': emerging role of the kinesin family member genes in birth defects. J Med Genet. 2020;57(12):797-807.
1. Novas R, Cardenas-Rodriguez M, Lepanto P, et al. Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B. Sci Rep. 2018;8(1):3019.
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De novo heterozygous variants in KIF5B cause kyphomelic dysplasia

Affiliations

De novo heterozygous variants in KIF5B cause kyphomelic dysplasia

Authors

Affiliations

Abstract

References

REFERENCES

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous