We describe a third patient with brain small vessel disease 3 (BSVD3), being the first with a homozygous essential splice site variant in the COLGALT1 gene, with a more severe phenotype than the 2 children reported earlier.

Analysis of whole exome sequencing (WES) data of the child and parents was performed. We validated the missplicing of the homozygous variant using reverse transcription PCR and Sanger sequencing of the mRNA in a lymphocyte culture.

The patient presented antenatally with porencephaly on ultrasound and MRI. Postnatally, he showed a severe developmental delay, refractory epilepsy, spastic quadriplegia, and a progressive hydrocephalus. WES revealed a homozygous canonical splice site variant NM_024656.3:c.625-2A>C. PCR and Sanger sequencing of the mRNA demonstrated that 2 cryptic splice sites are activated, causing a frameshift in the major transcript and in-frame deletion in a minor transcript.

We report a third patient with biallelic pathogenic variants in COLGALT1, confirming the role of this gene in autosomal recessive BSVD3.

我们描述了第三名患有脑小血管疾病 3 (BSVD3) 的患者，该患者是第一位在COLGALT1基因中具有纯合必需剪接位点变异的患者，其表型比之前报道的 2 名儿童更严重。

对孩子和父母的全外显子组测序（WES）数据进行了分析。我们使用逆转录PCR和淋巴细胞培养物中mRNA的Sanger测序验证了纯合变体的错误剪接。

患者在产前超声和 MRI 上表现为前脑畸形。出生后，他表现出严重的发育迟缓、难治性癫痫、痉挛性四肢瘫痪和进行性脑积水。WES 揭示了纯合规范剪接位点变体 NM_024656.3:c.625-2A>C。mRNA 的 PCR 和 Sanger 测序表明 2 个隐秘的剪接位点被激活，导致主要转录本中的移码和次要转录本中的框内缺失。

我们报告了第三例COLGALT1 双等位基因致病变异的患者，证实了该基因在常染色体隐性 BSVD3 中的作用。