International students' perspectives on the genetic counseling application process.

Between 2018 and 2023, one percent of matched applicants to North American genetic counseling graduate programs (GCGPs) have been international applicants (IAs). The COVID-19 pandemic led to changes in the GCGP application processes in 2020, most notably the incorporation of virtual interviews and GRE waivers, which uniquely impacted IAs. Twelve international genetic counseling (GC) students who matriculated into a U.S.-based GCGP in 2021 or 2022 participated in this qualitative study (42% of the total enrolled) to understand their application experience. Cost, location of the program, and rapport during interviews were the most important factors identified by IAs to apply to and rank the GCGPs. Shadowing and volunteer experiences relevant to GC were cited as important for applicants to learn about a genetic counseling career, but many had challenges finding opportunities in their home countries. Unique logistical challenges in taking the GRE, transcript evaluation services, and standardized English proficiency tests were described. Although virtual interviews offered the same experience as domestic applicants, the time difference was a major challenge, requiring IAs to interview through the night, creating additional stressors. Nine of 12 were re-applicants and shared that engaging with GCGPs early in the process was beneficial for improving applications and, at times, requesting waivers for transcript evaluation requirements and considering unique volunteering experiences. Participants suggested GCGPs can address barriers by providing more specific information on their websites as it pertains to IAs, and contact information for the international student office. Improving awareness of the applicants' backgrounds, home country experiences, and time zone differences would provide IAs with a more equitable application experience. Addressing these barriers could help promote diversity, equity, and inclusion allowing for more IAs and the growth of the genetic counseling profession.

Pseudoachondroplasia: Phenotype and genotype in 11 Indian patients.

Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by rhizomelic short-limbed skeletal dysplasia. The primary clinical and radiographic features include disproportionate dwarfism, joint laxity and hyperextensibility, exaggerated lumbar lordosis, and late ossification of the epiphyses. Identification of disease-causing variants in heterozygous state in COMP establishes the molecular diagnosis of PSACH. We examined 11 families with clinical features suggestive of PSACH. In nine families, we used Sanger sequencing of exons 8-19 of COMP (NM_000095.2) and in two families exome sequencing was used for confirming the diagnosis. We identified 10 de novo variants, including five known variants (c.925G>A, c.976G>A, c.1201G>T, c.1417_1419del, and c.1511G>A) and five variants (c.874T>C, c.1201G>C, c.1309G>A, c.1416_1421delCGACAA, and c.1445A>T) which are not reported outside Indian ethnicity. We hereby report the largest series of individuals with molecular diagnosis of PSACH from India and reiterate the well-known genotype-phenotype corelation in PSACH.

Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.

Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.

A novel sequence variant in SFRP4 causing Pyle disease.

Pyle disease (PYL) is an extremely rare disorder of irregular development of long bone. Recently, homozygous mutations in secreted frizzled-related protein 4 gene (SFRP4) gene were found to underlie this condition. Sequencing of coding regions of SFRP4 gene from an 11-year-old female with PYL was performed. A novel homozygous nonsense variant, c.183C>G (p.Y61*) was observed. Segregation analysis in the patient revealed a germline mutation, resulting in reduced protein formation. This is the second report from a fourth affected family with a SFRP4 mutation causing PYL disease.