Disclaimer: This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay-Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase "expanded carrier screening" is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency. This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.

Cytokinesis in somatic cells concludes with the formation of a midbody, which is abscised to form individual daughter cells. In contrast, germ cell cytokinesis results in a permanent intercellular bridge connecting the daughter cells through a large cytoplasmic channel. During spermatogenesis, proposed roles for the intercellular bridge include germ cell communication, synchronization, and chromosome dosage compensation in haploid cells. Although several essential components of the midbody have recently been identified, essential components of the vertebrate germ cell intercellular bridge have until now not been described. Herein, we show that testis-expressed gene 14 (TEX14) is a novel protein that localizes to germ cell intercellular bridges. In the absence of TEX14, intercellular bridges are not observed by using electron microscopy and other markers. Spermatogenesis in Tex14 ؊/؊ mice progresses through the transit amplification of diploid spermatogonia and the expression of early meiotic markers but halts before the completion of the first meiotic division. Thus, TEX14 is required for intercellular bridges in vertebrate germ cells, and these studies provide evidence that the intercellular bridge is essential for spermatogenesis and fertility.cytoplasmic bridges ͉ knockout mouse ͉ male infertility ͉ male sterility ͉ ring canals

Spermatogonial self-renewal and differentiation are essential for male fertility and reproduction. We discovered that germ cell specific genes Sohlh1 and Sohlh2, encode basic helix-loop-helix (bHLH) transcriptional regulators that are essential in spermatogonial differentiation. Sohlh1 and Sohlh2 individual mouse knockouts show remarkably similar phenotypes. Here we show that SOHLH1 and SOHLH2 proteins are co-expressed in the entire spermatogonial population except in the GFRA1+ spermatogonia, which includes spermatogonial stem cells (SSCs). SOHLH1 and SOHLH2 are expressed in both KIT negative and KIT positive spermatogonia, and overlap Ngn3/EGFP and SOX3 expression. SOHLH1 and SOHLH2 heterodimerize with each other in vivo, as well as homodimerize. The Sohlh1/Sohlh2 double mutant phenocopies single mutants, i.e., spermatogonia continue to proliferate but do not differentiate properly. Further analysis revealed that GFRA1+ population was increased, while meiosis commenced prematurely in both single and double knockouts. Sohlh1 and Sohlh2 double deficiency has a synergistic effect on gene expression patterns as compared to the single knockouts. SOHLH proteins affect spermatogonial development by directly regulating Gfra1, Sox3 and Kit gene expression. SOHLH1 and SOHLH2 suppress genes involved in SSC maintenance, and induce genes important for spermatogonial differentiation.

We present evidence that a subset of mRNAs in the human parasitic trematode Schistosoma mansoni contain an identical 36-nucleotide spliced leader (SL) sequence at their 5' termini. The SL is derived from a 90-nucleotide nonpolyadenylylated RNA (SL RNA), presumably by trans-splicing.Neither the SL nor the SL RNA share significat sequence identity with previously described trans-spliced leaders and SL RNAs in trypanosomatid protozoans or nematodes. However, several features, such as predicted secondary structure, trimethylguanosine cap, and potential Sm binding site, suggest similarities among SL RNAs in widely divergent organisms. Our evidence also indicates that the exon 3 acceptor site of the 3-hydroxy-3-methylglutaryl-CoA reductase gene can be spliced either to the SL by trans-splicing or to an upstream exon, 2, by cis-splicing. The presence of a SL sequence in S. mansoni, a member of the phylum Platyhelminthes, suggests that transsplicing may be a common feature ofother lower invertebrates.Trans-splicing ofpre-mRNA sequences was first described in trypanosomatid protozoans (1-3). In these organisms, small nonpolyadenylylated RNAs [spliced leader (SL) RNAs] of -100 nucleotides (nt) donate a 5'-terminal 39-nt SL sequence to all pre-mRNAs to form the 5' termini of mature mRNAs. In metazoans, the description of trans-splicing has been confined to the phylum Nematoda. Trans-splicing in nematodes resembles the situation in trypanosomes as exemplified by the detection of Y-branched intermediates and the presence of consensus 5' and 3' splice sites flanking the SL and pre-mRNAs, respectively (4-6). There are, however, several notable differences. Unlike trypanosomatid protozoans, only a subset of nematode mRNAs (10-15%) mature via addition of a distinct 22-nt SL sequence (7). In addition, processing of nematode mRNA includes both cis-and trans-splicing (4). Analyses ofthese mRNAs and corresponding genomic clones have suggested that only the first exon serves as an acceptor for the 22-nt SL sequence (8).The discovery of trans-splicing in nematodes raised the question of the prevalence of this reaction in other metazoans. Nucleotide sequence analysis of SL genes in different genera of nematodes has revealed perfectly conserved copies of the 22-nt SL sequence (7, 9, 10). The nematode SL, however, does not hybridize to RNA from other metazoans such as Schistosoma mansoni, Dictyostelium, Drosophila, Xenopus, and humans (7). If these organisms process their mRNAs by trans-splicing, it is likely to involve SL sequences that are not homologous to the nematode SL.Here we present evidence that a subset of polyadenylylated transcripts in the human parasite S. mansoni, a trematode, are processed art their 5' termini by addition of a distinct 36-nt SL sequencet that shares no sequence identity with the 22-nt SL in nematodes or the 39-nt SL in trypanosomatid protozoans. Trematodes, cestodes, turbellarians, and monogeneans are grouped together into the morphologically diverse phylum Platyhelminthes and are distinctly differ...