What is the right sequencing approach? Solo VS extended family analysis in consanguineous populations.

Testing strategies is crucial for genetics clinics and testing laboratories. In this study, we tried to compare the hit rate between solo and trio and trio plus testing and between trio and sibship testing. Finally, we studied the impact of extended family analysis, mainly in complex and unsolved cases. Three cohorts were used for this analysis: one cohort to assess the hit rate between solo, trio and trio plus testing, another cohort to examine the impact of the testing strategy of sibship genome vs trio-based analysis, and a third cohort to test the impact of an extended family analysis of up to eight family members to lower the number of candidate variants. The hit rates in solo, trio and trio plus testing were 39, 40, and 41%, respectively. The total number of candidate variants in the sibship testing strategy was 117 variants compared to 59 variants in the trio-based analysis. We noticed that the average number of coding candidate variants in trio-based analysis was 1192 variants and 26,454 noncoding variants, and this number was lowered by 50-75% after adding additional family members, with up to two coding and 66 noncoding homozygous variants only, in families with eight family members. There was no difference in the hit rate between solo and extended family members. Trio-based analysis was a better approach than sibship testing, even in a consanguineous population. Finally, each additional family member helped to narrow down the number of variants by 50-75%. Our findings could help clinicians, researchers and testing laboratories select the most cost-effective and appropriate sequencing approach for their patients. Furthermore, using extended family analysis is a very useful tool for complex cases with novel genes

A new case of Bainbridge-Ropers syndrome (BRPS): delineating the phenotype and review of literature

Background: Bainbridge-Ropers syndrome (BRPS) is characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, profound speech delays, and intellectual disability and dysmorphic features. It is an autosomal dominant condition caused by heterozygous mutations in the ASXL3 gene (OMIM #615115) on chromosome 18q12. As per the literature available, only 39 cases including the current patient were reported with BRPS across the globe. Case presentation: A 4-year-old girl with confirmed BRPS. She had the characteristic features of the disease including psychomotor delay, hypotonia, profound speech impairment, neonatal feeding difficulties, postnatal, and dysmorphic features. The array CGH and whole exome sequencing were negative, but the whole genome sequencing detected a novel heterozygous de novo insertion in the ASXL3 gene c.3592_3593insGAT; p.Leu1198X. Conclusion: With the advent of whole exome/genome sequencing we would expect to diagnose more cases of BRPS from different ethnic populations. Further clinical and functional studies are needed to delineate the long-term course of the disease and to elaborate on the exact role of the ASXL3 gene in brain development. [JBCGenetics 2019; 2(1.000): 65-69

Genetic carrier screening for disorders included in newborn screening in the Saudi population

Background: Inborn errors of metabolism (IEM) are prevalent autosomal recessive disorders in Saudi Arabia. Socio-economic factors, such as consanguineous marriages, play a role in the high rate of diseases. The government of Saudi Arabia created a newborn screening program (NBS) for the most prevalent disorders to facilitate early intervention and the prevention of severe complications. The study aimed to determine the carried pathogenic allele of the diseases included in the NBS and the most frequently carried phenotype in the Saudi population. Methodology: We performed targeted genetic screening for the genes associated with the IEM in the NBS. We used the results of the whole exome sequencing of 1,314 affected and unaffected individuals from 650 families. The results constitute the King Abdullah International Medical Research Center Genomic Database. Results: According to the data set, four diseases occurred most frequently in the Saudi population: adrenal hyperplasia, propionic acidemia, phenylketonuria, and maple syrup urine disease. In total, 12 pathogenic variants occurred frequently. Conclusion: This study generated an updated list of the most pathogenic variants in the Saudi population, based on the National Guard Hospital dataset. Additional research with larger data sets from the different regions will provide valuable information about the allele distribution in the Saudi population, creating a carrier screening program. [JBCGenetics 2021; 4(2.000): 70-75

Genetic impact of non-consanguineous marriages in Saudi Arabia.

Background: Physicians and geneticists face challenges in making accurate diagnoses during clinical evaluations; affecting patients and clinicians. The aim of this study was to estimate the hit rate of the non-consanguineous population. Moreover, prevalence of the genetic disorder in both the consanguineous and non- consanguineous population of Saudi Arabia at King Abdulaziz Medical City in Riyadh data. Methods: We reviewed 681 families and 1563 individuals with 2,565,335 variants in the King Abdullah International Medical Research Center (KAIMRC) Genomic Database (KGD), Riyadh, Saudi Arabia. All the ES requests were obtained from the physician and clinical geneticist of KAIMRC, and the test was performed either in-house or in a College of American Pathologists accredited laboratory center for clinical purposes. Results: A total of 151 non-consanguineous individuals with exome sequencing requests in the population genomic database of King Abdullah International Medical Research Center was considered for the study. In total, 27 had disease-causing variants, and the hit rate was 27/151 (18%). Among the 28 different variants in the 27 individuals, 50% were de novo variants and 50% inherited. The hit rate of the variants causing autosomal recessive disorders was 12/28 (42.8%), autosomal dominant disorders 13/28 (46.4%), and X-linked disorders 3/28 (10.7%). Conclusion: Non-consanguineous marriages have a lower risk of genetic disorders, and reducing consanguinity reduces the risk of genetic disorders by two to three times.   [JBCGenetics 2022; 5(2.000): 37-42

Supplementary testing after negative or inconclusive exome sequencing results

Background: Accurate diagnosis benefits patients and their families by directing clinical management; predicting recurrence risks; providing prognosis; and preventing the invasive, time-consuming, and costly diagnostic odyssey. The present study aimed at evaluating the usefulness and clinical utility of supplementary testing (deletion/duplication, targeted genome methylation analysis, and whole mitochondrial genome testing) after inconclusive or negative exome results and the outcome of the supplementary testing. Methods: A total of 3,505 clinical exome sequencing results were evaluated, and cases with supplementary testing were analyzed for the accuracy and validity of the supplementary testing. Results: The present study cohort comprised 26 cases where supplementary testing was ordered (12 inconclusive results and 14 negative results). Out of the 12 inconclusive results, only one case was positive for supplementary testing (1/12) and none of the negative cases (0/14). Conclusion: For most cases, supplementary testing to negative exome sequencing failed to identify any possible explanation of the disorder, concluding that supplementary testing has limited clinical utility. [JBCGenetics 2023; 6(1.000): 1-13