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.
- epilepsy and seizures
- obstetrics and gynaecology
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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.