The Invitae Isolated Gonadotropin-releasing Hormone Deficiency (IGD) Panel analyzes three genes that are associated with IGD and Kallmann syndrome, including ANOS1 (“KAL1”). These genes were selected based on the available evidence to date. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.
ANOS1 CHD7 FGFR1
ANOS1 CHD7 FGFR1
Isolated gonadotropin-releasing hormone deficiency (IGD) manifests as hypogonadism and low concentrations of gonadotropins (luteinizing and follicle-stimulating hormones). Approximately 60% of individuals with IGD have an impaired sense of smell—a presentation that is categorized as Kallmann syndrome. The remaining 40% have a normal (normosmic) sense of smell. Adults with IGD present with incomplete sexual maturation: males have decreased muscle mass, absence of secondary sexual characteristics, erectile dysfunction, and infertility whereas females exhibit primary amenorrhea and reduced or absent breast development. Low testosterone or estradiol in conjunction with low levels of LH/FSH confirms hypogonadotropic hypogonadism in affected individuals. Hypoplasia of the olfactory bulbs or tracts is common in Kallmann syndrome. Affected individuals are typically treated with hormone replacement therapies.
Approximately 20%–30% of isolated gonadotropin-releasing hormone deficiency is explained by ANOS1 (“KAL1”), CHD7, and FGFR1.
ANOS1-related (or “KAL1-related”) IGD is X-linked recessive. FGFR1- and CHD7-related IGD are autosomal dominant.
IGD has incomplete penetrance and variable expression. ANOS1-related (or “KAL1-related”) phenotypes are typically fully penetrant.
The prevalence is estimated at 1 in 8000 males and 1 in 40,000 females.
Testing should be considered for patients who have incomplete sexual maturation and are suspected to have hypogonadotropic hypogonadism.
For management recommendations please refer to:
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|