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Neurogenetics
Original research
Prenatal clinical manifestations in individuals with COL4A1/2 variants
  1. Toshiyuki Itai1,
  2. Satoko Miyatake1,2,
  3. Masataka Taguri3,
  4. Fumihito Nozaki4,
  5. Masayasu Ohta5,
  6. Hitoshi Osaka6,
  7. Masafumi Morimoto7,
  8. Tomoko Tandou8,
  9. Fumikatsu Nohara9,
  10. Yuichi Takami10,
  11. Fumitaka Yoshioka11,
  12. Shoko Shimokawa11,
  13. Jiu Okuno-Yuguchi12,
  14. Mitsuo Motobayashi12,
  15. Yuko Takei12,
  16. Tetsuhiro Fukuyama12,
  17. Satoko Kumada13,
  18. Yohane Miyata13,
  19. Chikako Ogawa14,
  20. Yuki Maki14,
  21. Noriko Togashi15,
  22. Teruyuki Ishikura16,
  23. Makoto Kinoshita16,
  24. Yusuke Mitani17,
  25. Yonehiro Kanemura18,
  26. Tsuyoshi Omi19,
  27. Naoki Ando20,
  28. Ayako Hattori20,
  29. Shinji Saitoh20,
  30. Yukihiro Kitai21,
  31. Satori Hirai21,
  32. Hiroshi Arai21,
  33. Fumihiko Ishida22,
  34. Hidetoshi Taniguchi23,
  35. Yasuji Kitabatake23,
  36. Keiichi Ozono23,
  37. Shin Nabatame23,
  38. Robert Smigiel24,
  39. Mitsuhiro Kato25,
  40. Koichi Tanda26,
  41. Yoshihiko Saito27,
  42. Akihiko Ishiyama27,
  43. Yushi Noguchi28,
  44. Mazumi Miura28,
  45. Takaaki Nakano29,
  46. Keiko Hirano30,
  47. Ryoko Honda31,
  48. Ichiro Kuki32,
  49. Jun-ichi Takanashi33,
  50. Akihito Takeuchi34,
  51. Tatsuya Fukasawa35,
  52. Chizuru Seiwa36,
  53. Atsuko Harada37,
  54. Yusuke Yachi38,
  55. Hiroyuki Higashiyama38,
  56. Hiroshi Terashima39,
  57. Tadayuki Kumagai39,
  58. Satoshi Hada40,
  59. Yoshiichi Abe41,
  60. Etsuko Miyagi42,
  61. Yuri Uchiyama1,43,
  62. Atsushi Fujita1,
  63. Eri Imagawa1,
  64. Yoshiteru Azuma1,
  65. Kohei Hamanaka1,
  66. Eriko Koshimizu1,
  67. Satomi Mitsuhashi1,
  68. Takeshi Mizuguchi1,
  69. Atsushi Takata1,
  70. Noriko Miyake1,
  71. Yoshinori Tsurusaki44,
  72. Hiroshi Doi45,
  73. Mitsuko Nakashima46,
  74. Hirotomo Saitsu46,
  75. Naomichi Matsumoto1
  1. 1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  2. 2 Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa, Japan
  3. 3 Department of Data Science, Yokohama City University School of Data Science, Yokohama, Kanagawa, Japan
  4. 4 Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Shiga, Japan
  5. 5 Department of Pediatrics, JA Toride General Medical Center, Toride, Ibaraki, Japan
  6. 6 Department of Pediatrics, Jichi Medical University, Shimotsuke, Tochigi, Japan
  7. 7 Division of Pediatrics, Department of Medical Science, School of Nursing, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
  8. 8 Department of Pediatrics, Yamanashi Prefectural Central Hospital, Kofu, Yamanashi, Japan
  9. 9 Department of Pediatrics, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
  10. 10 Department of Pediatrics, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
  11. 11 Department of Neurosurgery, Saga University, Saga, Saga, Japan
  12. 12 Division of Neurology, Nagano Children's Hospital, Azumino, Nagano, Japan
  13. 13 Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan
  14. 14 Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  15. 15 Department of Neurology, Miyagi Children's Hospital, Sendai, Miyagi, Japan
  16. 16 Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  17. 17 Department of Pediatrics, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
  18. 18 Department of Biomedical Research and Innovation, Institute for Clinical Research and Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka, Osaka, Japan
  19. 19 Department of Pediatrics, Okinawa Nanbu Medical Treatment and Education Center, Naha, Okinawa, Japan
  20. 20 Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan
  21. 21 Department of Pediatric Neurology, Bobath Memorial Hospital, Osaka, Osaka, Japan
  22. 22 Perinatal Center for Maternity and Neonate, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
  23. 23 Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  24. 24 Department of Pediatrics and Rare Disorders, Wroclaw Medical University, Wroclaw, Poland
  25. 25 Department of Pediatrics, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
  26. 26 Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Kyoto, Japan
  27. 27 Department of Child Neurology, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
  28. 28 Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
  29. 29 Department of Neurosurgery, Akiyama Neurosurgical Hospital, Yokohama, Kanagawa, Japan
  30. 30 Department of Pediatrics, Iwata City Hospital, Iwata, Shizuoka, Japan
  31. 31 Department of Pediatrics, National Hospital Organisation Nagasaki Medical Center, Omura, Nagasaki, Japan
  32. 32 Department of Child Neurology, Osaka City General Hospital, Osaka, Osaka, Japan
  33. 33 Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan
  34. 34 Division of Neonatology and Neuropediatrics, National Hospital Organization Okayama Medical Center, Okayama, Okayama, Japan
  35. 35 Department of Pediatrics, Anjo Kosei Hospital, Anjo, Aichi, Japan
  36. 36 Department of Pediatrics, Yamagata Prefectural Rehabilitation Center for Children with Disabilities, Kaminoyama, Yamagata, Japan
  37. 37 Department of Pediatric Neurosurgery, Takatsuki General Hospital, Takatsuki, Osaka, Japan
  38. 38 Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama, Toyama, Japan
  39. 39 Division of Neurology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
  40. 40 Department of Neonatology, Hiroshima Prefectural Hospital, Hiroshima, Hiroshima, Japan
  41. 41 Department of Pediatrics, Oita University Faculty Of Medicine, Yufu, Oita, Japan
  42. 42 Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  43. 43 Department of Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  44. 44 Faculty of Nutritional Science, Sagami Women's University, Sagamihara, Kanagawa, Japan
  45. 45 Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
  46. 46 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
  1. Correspondence to Professor Naomichi Matsumoto, Department of Human Genetics, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan; naomat{at}yokohama-cu.ac.jp

Abstract

Background Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.

Methods We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.

Results Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.

Conclusions Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

  • diagnostics
  • epilepsy and seizures
  • genetics
  • neurology
  • obstetrics and gynaecology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Additional material is published online only. To view, please visit the journal online.

https://doi.org/10.1136/jmedgenet-2020-106896

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. Additional material is published online only. To view, please visit the journal online.

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    Footnotes

    • Contributors Conceptualisation and methodology: TIt, SMiy and NMa; patients enrollment and writing their clinical summary: FNoz, MO, HO, MMor, TT, FNoh, YTaka, FY, SSh, JO-Y, MMot, YTake, TFuku, SK, CO, YMa, NT, TIs, MKi, YMit, YKa, TO, NA, AHat, SSa, YKitai, SHi, HA, FI, HTa, YKitab, KO, SN, YMiy, RS, MKa, KT, YS, AI, YN, MMiu, TN, KHi, RH, IK, JT, ATake, TFuka, CS, AHar, YY, HH, HTe, TK, SHa and YAb; data evaluation and validation: TIt, SMiy, YU, HS and NMa; data interpretation and analysis: TIt, SMiy, MT, YU, YAz, KHa, ATaka, HS and NMa; writing the original draft of the manuscript, figures and tables: TIt; review and editing of the draft: SMiy, EM, YU, AF, EI, YAz, KHa, EK, SMit, TM, ATaka, NMi, YTs, HD, MN, HS and NMa; project administration: NMa; funding acquisition: SMiy, NMi, HS and NMa; all authors read and approved the final manuscript before submission.

    • Funding This work was supported by AMED under grant numbers JP20ek0109280, JP20dm0107090, JP20ek0109301, JP20ek0109348 and JP20kk0205012; by JSPS KAKENHI under grant numbers JP17H01539, JP19H06321, JP17K10080, 17K15630, 17K16132 and 16H05160; grants from the Ministry of Health, Labour and Welfare (NM); the Takeda Science Foundation (HS, NM and NM); and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics (SM).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.