Abstract: PD08-04
Sources of Funding: Hussman Institute for Human Genomics_x000D_ _x000D_ _x000D_

Introduction

Up to 80% of patients with a diagnosis of nonobstructive azoospermia (NOA) have a negative result on genetic testing. We sequenced the exomes of a consanguineous Turkish family comprised of the mother and father, who are cousins, and their four sons. Two sons had NOA and two had chest wall deformities and oligospermia. Standard genetic testing revealed no karyotype abnormalities or Y microdeletions. Using whole exome sequencing (WES) data and homozygosity mapping we sought to investigate the genetic cause of abnormal semen parameters in the sons._x000D_ _x000D_

Methods

Extraction of DNA was performed from blood samples followed by whole exome sequencing. Variants were annotated using the ANNOVAR software tool. The filter based annotation feature was used to assess variants for rarity, deleterious nature, conservation, and confirmed familial segregation as well as absence in the control population. _x000D_ _x000D_

Results

A non?synonymous mutation in “four?and?a?half lim domains 1� (FHL1) was identified in this consanguineous family from Turkey. This mutation in exon 6 (Xchr:135292164 G>A) of FHL1 is a nonsynonymous SNP and likely a disease?causing mutation as it is predicted to be damaging (SIFT 0.026, mutation taster score 1/D, and Polyphen2 0.846), is a rare variant (ExAC allele frequency of 1.11%), segregates with the disease, and is highly conserved (GERP 5.57). Family segregation of the variants showed the presence of the homozygous mutation in the brothers with NOA and low sperm counts, heterozygous mutation in the mother, and homozygous wild type in the father indicating an X?linked inheritance pattern.

Conclusions

Using WES, we identified an X linked mutation in FHL1 as a likely disease?causing variant in a Turkish family with two sons diagnosed with NOA. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases, where conventional genetic approaches have previously failed to define a genetic diagnosis.

Funding

Hussman Institute for Human Genomics_x000D_ _x000D_ _x000D_