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Novel exon-skipping variant disrupting the basic domain of HCFC1 causes intellectual disability without metabolic abnormalities in both male and female patients

Journal of Human Genetics volume 66, pages 717–724 (2021)Cite this article

Abstract

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.

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Acknowledgements

We thank the patients and their families for their cooperation with this case report. We also thank Mrs. Marisa Andrews, CGC, who coordinated patients’ care and genetic testing.

Author information

Authors and Affiliations

  1. Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, USA

    Parith Wongkittichote & Marwan S. Shinawi

  2. Division of Newborn Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, USA

    Daniel J. Wegner

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Contributions

PW and MS designed and conceptualized the study and performed clinical analysis of the patients. PW drafted the manuscript. DW performed molecular studies and interpreted the molecular data. All authors were involved with revising the manuscript. MS supervised the study and obtained consents.

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Correspondence to Marwan S. Shinawi.

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The authors declare that they have no conflict of interest.

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The guardian of patients IV-1 and IV-2 signed a consent form of Washington University Institutional Review Board (IRB) approved protocol entitled: “Molecular and Cytogenetic Testing for Genetic Diseases; IRB ID #: 201102465). All subjects or their guardians signed a consent form for publication approved by Washington University IRB (Media Authorization for the Use and Disclosure of Protected Health Information).

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Wongkittichote, P., Wegner, D.J. & Shinawi, M.S. Novel exon-skipping variant disrupting the basic domain of HCFC1 causes intellectual disability without metabolic abnormalities in both male and female patients. J Hum Genet 66, 717–724 (2021). https://doi.org/10.1038/s10038-020-00892-9

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