The Invitae MED12-related disorders test analyzes the MED12-related gene, which are associated with FG syndrome type 1 (FGS1), Lujan syndrome and other MED12 spectrum disorders. MED12-related conditions are characterized by hypotonia, abnormalities of the corpus callosum, intellectual disability, and behavioral problems.
Previously, traditional testing strategies for MED12-related disorders included initial testing of exons 21 and 22 of the MED12 gene to evaluate for p.Arg961Trp (the recurring pathogenic variant for FGS1) and for other reported MED12 variants; when this initial testing was negative, sequence analysis of the remaining exons would have been considered. The Invitae MED12-related disorders test analyzes the full coding region of the MED12 gene and eliminates the need for the former tiered-test approach.
Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.
MED12-related conditions are multisystemic developmental disorders and generally characterized by hypotonia, abnormalities of the corpus callosum, intellectual disability, and behavioral problems. Affected individuals may also present with physical abnormalities including macrocephaly, distinctive facial features, anal abnormalities, broad thumbs, and big toes. Additional clinical findings may include heart defects, seizures, inguinal hernia, and undescended testes in males. The clinical presentation is variable; not all individuals with MED12-related disorders will present with every characteristic described above.
The clinical sensitivity for this test has not yet been determined.
MED12-related disorders are inherited in an X-linked manner.
The penetrance of MED12-related conditions is presumed to be 100% in males. To date, the published variants in MED12 (p.Arg961Trp, p.Gly958Glu, and p.Asn1007Ser) have not been observed in unaffected males. The clinical presentation is variable. Female carriers are typically unaffected.
The prevalence of MED12-related conditions is currently unknown.
Although formal diagnostic criteria have not been established for MED12-related conditions, the following clinical findings are suggestive of a clinical diagnosis: small ears, distinctive facial features (tall forehead; down-slanted palpebral fissures; long, narrow face), congenital anomalies (heart or skeletal defects; abnormality of the corpus callosum), macrocephaly, low muscle tone, and a characteristic eager-to-please behavior.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|