A novel missense variant in LAMC1 identified in a POI family by whole exome sequencing

Abstract

Objective

This study aimed to identify novel pathogenic genes and variants in a Chinese family with premature ovarian insufficiency (POI).

Methods

A Chinese POI family was enrolled in this study. Whole exome sequencing was performed on the proband and her mother to identify the potential causative genes and variants and Sanger sequencing was used to confirm the finally identified potential pathogenic variant in the family.

Results

An assessment of the family pedigree suggested that POI was inherited in an autosomal dominant manner in this family. A novel missense variant of the laminin subunit gamma-1 gene (LAMC1; NM_002293.4: c.3281A > T, p.D1094V) was finally identified in the proband and her affected mother. This variant was not found in any public databases. In silico analysis indicated the amino acid encoded at the variant site was highly conserved among mammals and associated with decreased protein stability and disrupted protein function. Its presence in the POI family was confirmed by Sanger sequencing.

Conclusions

This study firstly reported a novel missense variant of LAMC1 in a Chinese POI family, which was inherited in an autosomal dominant manner. This variant may result in the development of POI. Our results provide supporting evidence for a causative role for LAMC1 variants in POI.

Keywords:

• Premature ovarian insufficiency
• whole exome sequencing
• LAMC1
• missense variant
• autosomal dominant

Acknowledgements

We would like to acknowledge all participants in this study.

Authors’ contributions

All authors contributed to the study conception and design. HFX and YGF collected the clinical samples and performed the clinical diagnosis. BBW, CYW and HW analyzed WES data. The validation experiment was performed by TYL. The first draft of the manuscript was written by CYW and HFX. All authors reviewed the manuscript.

Disclosure statement

The authors declare that they have no competing interests.

Data availability statement

All data used during the study are available from the corresponding author on reasonable request.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (No. 81904308) and CAMS Innovation Fund for Medical Sciences (2018-I2M-1-004).