Identification of two aberrant transcripts by RNA sequencing for a novel variant c.3354 + 5 G > A of MED12 in a Chinese girl with non-syndromic intellectual disability

Abstract

Background: Missense variants in MED12 are associated with MED12-related disorders. We aimed to clarify the molecular level changes and underlying pathogenic mechanism of a female patient in our study.

Methods: We reported a Chinese girl with clinical characteristics similar to MED12-related disorders. Trio whole exome sequencing (WES) was performed to identify related pathogenic variant(s) and RNA sequencing (RNA-seq) was subsequently applied to evaluate the effect of identified variant(s) on mRNA splicing. Moreover, X-chromosome inactivation (XCI) assay based on AR and RP2 was performed to reveal the XCI pattern of the female patient.

Results: The proband manifested mainly as mental retardation and language impairment. Trio WES revealed a novel heterozygous variant c.3354 + 5 G > A in intron 23 of MED12. RNA-seq identified two aberrant transcripts. XCI assay on AR revealed a homozygous result, while XCI based on RP2 showed random pattern in peripheral blood.

Conclusion: In conclusion, we identified a novel variant c.3354 + 5 G > A by WES combined with RNA-seq, which extends the spectrum of MED12 variants and provide a basis for further genetic counseling. According to the result of two aberrant transcripts by RNA-seq, we speculate that our patient's milder clinical feature may be the consequence of multiple different transcripts.

Keywords: MED12 gene; Multiple transcripts; Non-syndromic intellectual disability; Splicing variant; X-chromosome inactivation.