Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella.

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe type of teratozoospermia. In this study, whole-exome sequencing was conducted on 55 patients with MMAF, and biallelic mutations of CFAP58 were identified in two patients. The variants are rare and pathogenic, and CFAP58 was absent in the CFAP58-mutated sperm. The F037/II:1 couple benefited from intracytoplasmic sperm injection (ICSI). This study further indicated that CFAP58 is a pathogenic gene associated with MMAF and ICSI is an effective treatment.

Pedigree analysis of two brothers with severe oligozoospermia caused by maternal inv(X) (p22.3, q22) chromosome abnormality.

Sex chromosome abnormality (SCA) is one of the major causes of male spermatogenesis dysfunction. In our study, we sought to investigate the novel X chromosome inversion leading to severe oligozoospermia. Here, we report two brothers with severe oligozoospermia without any other abnormal clinical phenotype. The chromosome karyotypes in peripheral blood of both brothers were 46, Y, inv (X) (p22.3, q22), and no Y chromosome microdeletion was found. The karyotype of their mother was 46, X, inv (X) (p22.3, q22) and that of their father was 46, XY. This is the first report in China that X chromosomal inversion, 46, Y, inv (X) (p22.3, q22), is associated with severe oligozoospermia. This inversion may be a direct genetic risk factor for spermatogenesis.

Comprehensive Genome Profiling of Single Sperm Cells by Multiple Annealing and Looping-Based Amplification Cycles and Next-Generation Sequencing from Carriers of Robertsonian Translocation.

Robertsonian translocation (RT) is a common cause for male infertility, recurrent pregnancy loss, and birth defects. Studying meiotic recombination in RT-carrier patients helps decipher the mechanism and improve the clinical management of infertility and birth defects caused by RT. Here we present a new method to study spermatogenesis on a single-gamete basis from two RT carriers. By using a combined single-cell whole-genome amplification and sequencing protocol, we comprehensively profiled the chromosomal copy number of 88 single sperms from two RT-carrier patients. With the profiled information, chromosomal aberrations were identified on a whole-genome, per-sperm basis. We found that the previously reported interchromosomal effect might not exist with RT carriers. It is suggested that single-cell genome sequencing enables comprehensive chromosomal aneuploidy screening and provides a powerful tool for studying gamete generation from patients carrying chromosomal diseases.

Use of targeted sequence capture and high-throughput sequencing identifies a novel PKD1 mutation involved in adult polycystic kidney disease.

Polycystic kidney disease (PKD) is a common inherited disease that is characterized by a progressive development of renal cysts. Approximately 85% of PKD cases are due to mutations in the polycystin 1 (PKD1) gene. Here, we report a pedigree containing nine patients with autosomal dominant PKD (ADPKD). Using targeted exome sequencing of PKD1 and PKD2 genes, we identified a novel heterozygous frameshift mutation c.3976_3977insCT (p.F1326Sfs*21) in the PKD1 gene that segregated between affected and unaffected family members. This mutation is currently not present in the 1000 Genomes Project nor ExAC databases and is therefore a novel PKD1 mutation involved in ADPKD. These results provide a novel sequence variant for the genetic analysis of this disease.

A Case of Bilateral Testicular Tumors Subsequently Diagnosed as Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

21-hydroxylase deficiency (21-OHD) caused congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic disorders resulting from mutations in genes involved with cortisol (CO) synthesis in the adrenal glands. Testicular adrenal rest tumors (TARTs) are rarely the presenting symptoms of CAH. Here, we describe a case of simple virilizing CAH with TARTs, in a 15-year-old boy. The patient showed physical signs of precocious puberty. The levels of blood adrenocorticotropic hormone (ACTH), urinary 17-ketone steroids (17-KS), dehydroepiandrosterone sulfate (DHEA-S), and serum progesterone (PRGE) were elevated, whereas those of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and CO were reduced. Computed tomography (CT) of the adrenal glands and magnetic resonance imaging (MRI) of the testes showed a soft tissue density (more pronounced on the right side) and an irregularly swollen mass (more pronounced on the left side), respectively. Pathological examination of a specimen of the mass indicated polygonal/circular eosinophilic cytoplasm, cord-like arrangement of interstitial cells, and lipid pigment in the cytoplasm. Immunohistochemistry results precluded a diagnosis of Leydig cell tumors. DNA sequencing revealed a hackneyed homozygous mutation, I2g, on intron 2 of the CYP21A2 gene. The patient's symptoms improved after a three-month of dexamethasone therapy. Recent radiographic data showed reduced hyperplastic adrenal nodules and testicular tumors. A diagnosis of TART should be considered and prioritized in CAH patients with testicular tumors. Replacement therapy using a sufficient amount of dexamethasone in this case helps combat TART.