228 recessive genetic disorders identified by Hiro Clinic

228 carrier screening tests developed by the Medicover Genetics Ltd laboratory.
Genomic deoxyribonucleic acid (gDNA) is extracted using standardised methods and mechanically fragmented prior to DNA library preparation.
DNA enrichment of the genomic region of interest is performed using solution-based hybridisation methods and sequenced next-generation sequencing (NGS).
The read-out sequence data is referenced to a reference genome and mutations are identified using a proprietary bioinformatics pipeline.
Recessive inheritance can be identified for single nucleotide variants, small insertions and deletions (≤30 bases) and copy number variations (CNVs).
Variants are classified according to the American College of Medical Genomics and Genomics 3-5 criteria.
Variant classification and interpretation is performed using the Varsome Clinical platform and is based on information available at the time of testing.
Only pathogenic and suspected pathogenic mutations are reported. Variants of detected but unknown significance, benign or potentially benign mutations are not reported.
Genetic counselling is recommended for clinical interpretation and results.
A: If autosomal results are:
A-1: “No clinically significant variants detected”
While not a complete guarantee that the testee is not a carrier of a genetic disease, they indicate the absence of a genetic variant and are unlikely to be a carrier.
A-2: ‘Clinically significant variant detected’
Indicates that a genetic alteration has been identified and that the testee is a carrier of the disease.
The person can then be a carrier of two or more diseases.
Carriers usually do not have symptoms of the disease.
However, two genes on two chromosomes may both be abnormal, in which case the possibility that the testee is currently affected or will be in the future cannot be ruled out.
B: For X-linked inherited diseases:
B-1: ‘No clinically significant variant detected’
Indicates the absence of a heritable variant, and can be said to indicate that the testee is not affected if the testee is male, or is unlikely to be a carrier if the testee is female, but it cannot be ruled out completely.
B-2: ‘Clinically significant variant detected’:
Indicates that a genetic alteration has been identified. In the case of female test subjects, it is possible that they are carriers.
If the testee is male, it indicates that he is currently affected or may develop the disease in the future.
However, the disease groups in this panel vary in severity and may not present clinically.
The aim of the test is to detect all variants associated with the detected gene by targeting all coding exons, MANE and/or standard transcripts and 10 bp of adjacent intronic sequences.
Mutants outside the target region are not intended to be detected by this assay.
Unless otherwise stated, sequence changes (SNVs and INDELS) in promoters and other non-coding regions are not detected by this assay.
Specific sequence changes (SNVs and INDELS) in non-coding regions considered clinically important for the detected gene are included in the analysis.
If two variants are identified in a gene, it is not possible to distinguish whether these are on one chromosome (cis) or another (trans).
Genetic changes such as inversion, rearrangements, ploidy and epigenetic effects are not covered by this test.
Certain sequence variations in target regions, including repetitive sequences (SNVs and INDELS), highly homologous sequences such as segmental duplications and pseudogenes, and regions of high/low GC content may not be detected.
Copy Number Variations (CNVs) are calculated using high-quality sequencing reads that are free of duplicates and uniquely aligned.
CNVs are detected for a subset of target regions using GC content normalisation and depth of sequencing coverage approach.
CNV anomalies are detected if the detected coverage deviates significantly from the coverage estimated from the reference site.
CNVs can be detected down to a resolution of a few exon levels.
If the CNV is positive, it is confirmed using the orthogonal method.
CNVs cannot be detected in genomic regions that contain little or no mapping, repetitive sequences, pseudogenes or high/low GC content.
Detecting CNVs using NGS is less sensitive/specific than orthogonal quantification methods, so the absence of a reported CNV does not guarantee that it is not present.
The fact that no disease-causing variants are present in a target gene reduces the likelihood of disease, but does not completely exclude the possibility of disease-related syndromes.

Validation testing is carried out by Medicaver Genetics Ltd.
The test does not identify all mutations associated with the disease tested.
While the test is highly accurate, the possibility of false positives or false negatives still exists and can be caused by technical or biological limitations.
These include rare genetic variants, mosaicism, blood transfusions, bone marrow transplants or other rare molecular events.
Some undetected genetic alterations may be affected and are not tested by carrier screening tests.
Although genetic testing is an important part of the diagnostic process, genetic testing does not always give definitive answers. In some cases, a genetic mutation may be present but not identified by testing.
This is due to limitations in current medical knowledge or testing techniques.
Concurrent use of other clinical data and clinical findings is recommended.
Resulting results should always be considered in relation to other clinical findings.
The clinician who referred the patient for testing is responsible for pre- and post-test counselling, including advice on the need for additional genetic testing.
Other diagnostic tests may be required.