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Non-Canonical Splice Site Variant in FREM1 Result in Fetal Renal Agenesis

Xingyu Feng1, Yao Hu1, Xiaojuan Wang2

  • 1Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.

Clinical Genetics
|July 3, 2025
PubMed

Insights

Loss-of-function variants in the FREM1 gene can cause severe developmental disorders. This study identifies novel FREM1 variants, including a splice site mutation, in a case of bilateral renal agenesis, expanding the known FREM1-related disease spectrum.

Area of Science:

  • Genetics
  • Developmental Biology
  • Medical Research

Background:

  • Loss-of-function variants in the FREM1 gene are associated with Manitoba oculotrichoanal (MOTA) and bifid nose, renal agenesis, and anorectal malformations (BNAR) syndromes.
  • The full spectrum of phenotypes caused by FREM1 variants is not yet fully understood.

Purpose of the Study:

  • To investigate the genetic basis of bilateral renal agenesis in a prenatal case.
  • To characterize the functional impact of identified FREM1 variants.

Main Methods:

  • Whole exome sequencing was performed on a prenatal case with bilateral renal agenesis.
  • Minigene assays and bioinformatic analyses were used to assess the effect of a splice site variant.

Main Results:

  • Compound heterozygous variants in the FREM1 gene were identified: c.5622G>A (p.Trp1874*) and c.3274+4A>G (p.Gly1030_Ile1091del).
  • The splice site variant was confirmed to cause aberrant splicing and affect gene expression levels.
  • These findings link non-canonical splice site variants in FREM1 to bilateral renal agenesis.

Conclusions:

  • Novel FREM1 variants, including a non-canonical splice site mutation, contribute to bilateral renal agenesis.
  • This study expands the phenotypic spectrum associated with FREM1 gene variants.
  • Aberrant splicing due to FREM1 variants plays a significant role in the pathogenesis of bilateral renal agenesis.
Keywords:
FREM1minigene analysisrenal agenesissplice site variant

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