Novel inactivating mutations of the DCAF17 gene in American and Turkish families cause male infertility and female subfertility in the mouse model.

Loss-of-function DCAF17 variants cause hypogonadism, partial alopecia, diabetes mellitus, mental retardation, and deafness with variable clinical presentation. DCAF17 pathogenic variants have been largely reported in the Middle Eastern populations, but the incidence in American families is rare and animal models are lacking. Exome sequencing in 5 women with syndromic hypergonadotropic hypogonadism from 2 unrelated families revealed novel pathogenic variants in the DCAF17 gene. DCAF17 exon 2 (c.127-1G > C) novel homozygous variants were discovered in 4 Turkish siblings, while 1 American was compound heterozygous for 1-stop gain variant in exon 5 (c.C535T; p.Gln179*) and previously described stop gain variant in exon 9 (c.G906A; p.Trp302*). A mouse model mimicking loss of function in exon 2 of Dcaf17 was generated using CRISPR/Cas9 and showed female subfertility and male infertility. Our results identify 2 novel variants, and show that Dcaf17 plays a significant role in mammalian gonadal development and infertility.

High-resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X-linked blue cone monochromacy.

The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.

Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure.

CONTEXT: Inactivating FSH receptor (FSHR) mutations can affect ovarian function, resulting in variable clinical presentations ranging from primary amenorrhea to premature menopause. FSHR mutations have been largely reported in the Finnish population, but in patients of Asian Indian descent, the incidence of FSHR mutations is extremely rare. CASE DESCRIPTION: Two female siblings of Indian descent were diagnosed with primary ovarian failure and hypergonadotropic hypogonadism. The daughters were the result of a consanguineous marriage between second cousins. A combination of comparative genomic hybridization plus single nucleotide polymorphism array and whole exome sequencing was conducted on the family to identify potential causative genetic variants. CONCLUSION: Both daughters were found to have a novel pathogenic variant in FSHR (c.1253T>G, p.Ile418Ser), inherited as an autosomal recessive trait from heterozygous parents. This loss of function mutation is located in exon 10 of FSHR affecting the second transmembrane helix of the FSHR protein. The transmembrane domain of FSHR is highly conserved across species and is involved in signal transduction. The FSHR c.1253T>G variant is next to a known pathogenic variant, rs12190966 (c.1255G>A, p.Ala419Thr), previously reported in a Finnish woman with primary amenorrhea.