CASE REPORT article
Front. Genet.
Sec. Genetics of Common and Rare Diseases
Compound heterozygous CEP152 c.3346-5T>C and chr15 deletion caused recurrent MCPH-SCKS in a Chinese pregnant woman during two consecutive pregnancies
Provisionally accepted
Tao Zhang1,2
Hua Yuan1,2Xiaoliang Shi1,2Yao He1,2
Hai-Tao Pan1,2Yongxing Zhong1,2Jintang Zhang1,2
Zhen Yang3Yunyan Ke4Yan Chen4Feng Zhang1,2*- 1Shaoxing Maternity and Child Health Care Hospital, Shaoxing, China
- 2Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
- 3Clinic Lab BGI Genomics, Shanghai, China
- 4Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, China
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Background: Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS) are a group of autosomal recessive conditions characterized by severe growth retardation and neurodevelopmental impairment. CEP152 variants are established causes of both microcephaly and Seckel syndrome phenotypes, but the pathogenicity of different variant combinations and their clinical recurrence patterns require further verification with additional cases. Methods: Clinical and genetic analyses were performed for two consecutive pregnancies of a non-consanguineous Chinese couple. Fetal phenotypes were evaluated by ultrasound and fetal MRI sequentially; copy number variation sequencing (CNV-seq) was used to detect large genomic variants, whole-exome sequencing (WES) to screen for point variants, and minigene splicing assays to characterize the functional impact of key variants. Results: Fetuses in both pregnancies were diagnosed with MCPH-SCKS and harbored identical compound heterozygous CEP152 variants: a paternally inherited splice-site variant c.3346-5T>C and a maternally inherited 129.6 kb chromosomal deletion localized to 15q21.1, encompassing the entire CEP152 gene. Minigene assays confirmed that the c.3346-5T>C variant caused aberrant splicing via intron retention and exon skipping, clarifying its pathogenicity. The second pregnancy in 2024 independently verified the pathogenicity of this variant combination and disease recurrence. Conclusions: This represents the first report of identical compound heterozygous CEP152 variants causing MCPH-SCKS in two consecutive pregnancies. The independent occurrence in the second pregnancy provides definitive evidence of these variants' pathogenicity and the 25% recurrence risk characteristic of autosomal recessive inheritance. Conclusions: This study is the first report of MCPH-SCKS recurrence in consecutive pregnancies caused by the compound heterozygous CEP152 variant combination of c.3346-5T>C and 15q21.1 deletion. Independent recurrence in the second pregnancy not only confirms the pathogenicity of this variant combination but also provides clinical evidence for the 25% recurrence risk of autosomal recessive disorders. Furthermore, this report underscores the critical importance of comprehensive genetic testing, including CNV analysis for the prenatal diagnosis of MCPH-SCKS, offering valuable guidance for genetic counseling and prenatal intervention in similar families.
Keywords: primary autosomal recessive microcephaly, Seckel syndrome, CEP152 gene, Wholeexome sequencing, prenatal diagnosis
Received: 13 Jun 2025; Accepted: 27 Oct 2025.
Copyright: © 2025 Zhang, Yuan, Shi, He, Pan, Zhong, Zhang, Yang, Ke, Chen and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Feng Zhang, zzffzhang@163.com
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