Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
Division of Newborn Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
J Hum Genet. 2021 Jul;66(7):717-724. doi: 10.1038/s10038-020-00892-9. Epub 2021 Jan 30.
HCFC1, a global transcriptional regulator, has been shown to associate with MMACHC expression. Pathogenic variants in HCFC1 cause X-linked combined methylmalonic acidemia and hyperhomocysteinemia, CblX type (MIM# 309541). Recent studies showed that certain variants in HCFC1 are associated with X-linked intellectual disability with mild or absent metabolic abnormalities. Here, we report five subjects (three males, two females) from the same family with a novel predicted loss of function HCFC1 variant. All five patients exhibit developmental delay or intellectual disability/learning difficulty and some dysmorphic features; findings were milder in the female as compared to male subjects. Biochemical studies in all patients did not show methylmalonic acidemia or hyperhomocysteinemia but revealed elevated vitamin B12 levels. Trio exome sequencing of the proband and his parents revealed a maternally inherited novel variant in HCFC1 designated as c.1781_1803 + 3del26insCA (NM_005334). Targeted testing confirmed the presence of the same variant in two half-siblings and maternal great uncle. In silico analysis showed that the variant is expected to reduce the quality of the splice donor site in intron 10 and causes abnormal splicing. Sequencing of proband's cDNA revealed exon 10 skipping. Further molecular studies in the two manifesting females revealed moderate and high skewing of X inactivation. Our results support previous observation that HCFC1 variants located outside the Kelch domain exhibit dissociation of the clinical and biochemical phenotype and cause milder or no metabolic changes. We also show that this novel variant can be associated with a phenotype in females, although with milder severity, but further studies are needed to understand the role of skewed X inactivation among females in this rare disorder. Our work expands the genotypes and phenotypes associated with HCFC1-related disorder.
HCFC1 是一种全球转录调节剂，已被证明与 MMACHC 表达有关。HCFC1 中的致病性变异导致 X 连锁联合甲基丙二酸血症和高同型半胱氨酸血症，CblX 型（MIM#309541）。最近的研究表明，HCFC1 中的某些变体与 X 连锁智力残疾有关，其代谢异常轻微或不存在。在这里，我们报告了来自同一家庭的五名患者（三名男性，两名女性），他们携带一种新的预测功能丧失的 HCFC1 变体。所有五名患者均表现出发育迟缓或智力残疾/学习困难和一些发育异常特征；与男性患者相比，女性患者的表现更为轻微。所有患者的生化研究均未显示甲基丙二酸血症或高同型半胱氨酸血症，但发现维生素 B12 水平升高。对先证者及其父母的三代外显子组测序显示 HCFC1 中存在一种新的母系遗传变异，命名为 c.1781_1803+3del26insCA（NM_005334）。靶向检测证实了两名半同胞和母亲的叔伯的相同变体的存在。计算机分析表明，该变体预计会降低 10 号内含子剪接受体位点的质量，并导致异常剪接。先证者 cDNA 的测序显示 10 号外显子跳过。在两名表现型女性中进一步的分子研究显示，X 染色体失活存在中度和高度偏斜。我们的结果支持先前的观察结果，即位于 Kelch 结构域之外的 HCFC1 变体表现出临床和生化表型的分离，并导致轻度或无代谢变化。我们还表明，这种新型变体可能与女性的表型相关，尽管严重程度较轻，但需要进一步研究来了解在这种罕见疾病中女性 X 染色体失活偏斜的作用。我们的工作扩展了与 HCFC1 相关疾病相关的基因型和表型。
