[CHARACTERIZATION OF THE INDICATIONS FOR PERFORMING GENE PANEL SEQUENCING TESTS IN A GENOMIC CENTER].

INTRODUCTION: Following the recent human genome revolution, novel technologies have been developed in the last decade enabling advanced sequencing tests, including genetic panel tests that focus on groups of specific genes associated with a certain medical condition (phenotype). Since the process of assembling a genetic panel may be complex and requires significant manpower and time, it is important to define the most common and requested panels, for gradual construction and introduction of panel tests starting with the most common. AIMS: Since no information was found in the literature defining the common panels, the aim of the study was to define the indications for performing a gene panel within the framework of the provided services, and to estimate their frequency. METHODS: Prospective data acquisition was performed by a party responsible for approval of panel tests within Clalit Health Services Organization. The indications for all approved panel tests were registered since the launch of Clalit's Genomic Center. The total number of indications was counted, and according to the Pareto principle, 20% of the most frequent indications were chosen. In addition, the indications were divided into main medical disciplines. RESULTS: Overall, 132 indications were recorded for approved gene panel tests; 20% of these indications, i.e. the first 26 indications in terms of frequency, covered 79.6% of the cases. The most frequent approved panels were epilepsy (10.4%, confidence interval (CI) 8.5-12.6%), Maturity-onset diabetes of the young (MODY) (9.6%, CI 7.8-11.7%), cardiomyopathy (8.3%, CI 6.6-10.3%) and hearing impairment (7.6%, CI 6.0-9.6%). The most common disciplines in descending order were neurological diseases (23.0%, CI 20.3-25.9%), endocrinology (13.1%, CI 11.1-15.6%), heart diseases (9.0%, CI 7.3-11.1%) and eye diseases (7.8%, CI 6.2-9.8%). CONCLUSIONS: A review of panel approvals at the Genomic Center of Clalit showed a number of frequent indications. DISCUSSION: We believe this information can be useful for the establishment of genomic laboratories, as well as for the improvement of the service to the patients, by enabling the referral for specific panel tests by medical experts who are not geneticists or genetic counselors, after appropriate training (such as the "Genetics First" program of Clalit).

Potential Founder Variants in COL4A4 Identified in Bukharian Jews Linked to Autosomal Dominant and Autosomal Recessive Alport Syndrome.

BACKGROUND: Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4. METHODS: The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing. RESULTS: Molecular diagnosis was confirmed in 20/38 patients, with each patient having at least one of the three disease-causing COL4A4 variants detected: c.338GA (p.Gly1008Arg), and c.871-6T>C. In addition, two patients were obligate carriers. Overall, there were 17 heterozygotes, 2 compound heterozygotes, and 3 homozygotes. Each variant was detected in more than one unrelated family. All patients had hematuria with/without proteinuria at referral, and the youngest patient with proteinuria (age 5 years) was homozygous for the c.338G>A variant. End-stage renal disease was diagnosed in two patients at the age of 38 years, a compound heterozygote for c.338G>A and c.871-6T>C. Hearing deterioration was detected in three patients, the youngest aged 40 years, all of whom were heterozygous for c.338G>A. CONCLUSION: This study unveils three novel disease-causing variants, c.3022G>A, c.871-6T>C, and c.338G>A, in the COL4A4 gene that are recurrent among Jews of Bukharian ancestry, and cause Alport syndrome in both dominant and recessive autosomal inheritance patterns.

Whole-exome sequencing in fetuses with central nervous system abnormalities.

OBJECTIVE: We describe our experience with whole-exome sequencing (WES) in fetuses with central nervous system (CNS) abnormalities following a normal chromosomal microarray result. METHODS: During the study period (2014-2017) 7 cases (9 fetuses) with prenatally diagnosed CNS abnormality, whose chromosomal microarray analysis was negative, were offered whole-exome sequencing analysis. RESULTS: A pathogenic or a likely pathogenic variant was found in 5 cases including a previously described, likely pathogenic de novo TUBA1A variant (Case #1); a previously described homozygous VRK1 variant (Case #2); an X-linked ARX variant (Case #3); a likely pathogenic heterozygous variant in the TUBB3 gene (Case #5). Finally, in two fetuses of the same couple (Case #6), a compound heterozygous state was detected, consisting of the NPHP1 gene deletion and a sequence variant of uncertain significance. Two additional cases had normal WES results. CONCLUSION: Whole-exome sequencing may improve prenatal diagnosis in fetuses with CNS abnormalities.