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Genetics of Perrault syndrome in a family with ten affected individuals

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Hearing loss and impaired fertility are each common disorders. Perrault syndrome is inherited as an autosomal recessive disorder characterized in 46,XX females by both bilateral mild to severe childhood sensorineural hearing loss  and ovarian dysfunction. Some affected individuals have a neurological impairment, including epilepsy and a developmental delay, often associated with brain white matter changes. To date, recessive variants of CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, PRORP, RMND1, and TWNK have been associated with Perrault syndrome.

 

Methods:
PKDF1779 is a multigeneration consanguineous family with ten affected individuals from Pakistan. Affected individuals of both sexes have bilateral, profound sensorineural hearing loss. Affected females also exhibit primary ovarian insufficiency. Biochemical testing indicates elevated FSH and LH and reduced estradiol levels which is consistent with hypergonadotropic hypogonadism. Genome wide SNP genotyping, exome sequencing and Sanger sequencing was performed on gDNA samples from family PKDF1779.

 

Results:
Genome-wide SNP genotyping was performed and a shared region of homozygosity on chromosome 1 was identified among the ten affected members of family PKDF1779. The multipoint LOD score is 6.03. Exome sequencing identified a likely causal variant of GPN2 c.363C>A, p.(His121Gln). Sanger sequencing confirmed co-segregation of the GPN2 variant with the phenotype. Besides the GPN2:p.(His121Gln) variant, we identified two additional families that are segregating GPN2:p.(Asn222Asp) variant.

 

Conclusion:
Overall, our data identified a novel gene-disease relationship of GPN2 with Perrault syndrome. In yeast, Gpn2 and Gpn3 are involved in the assembly of the RNA polymerase complex. Future studies of GPN2 will focus on its function(s) in mammalian inner ear and ovaries.

 

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