This test is for familial dysautonomia (FD), a developmental disorder of the sensory and autonomic nervous system that is caused by pathogenic variants in the ELP1 (formerly known as IKBKAP) gene.
Familial dysautonomia belongs to a larger family of hereditary sensory and autonomic neuropathies (HSANs). Given that HSANs are a heterogeneous group of disorders, identification of the underlying genetic cause may direct medical treatment, help predict outcome for the patient, and further clarify recurrence risk.
Familial dysautonomia (FD) is a progressive neurodegenerative disorder that affects both the sensory neurons and the neurons of the autonomic nervous system. Damage to the sensory neurons reduces sensitivity to feelings such as taste, pain, and temperature. Damage to the autonomic neurons affects the body’s ability to regulate involuntary body functions, including digestion and maintenance of heart rate, blood pressure, and body temperature.
Symptoms typically first present in infancy and include muscle weakness, gastrointestinal dysfunction, recurrent pneumonia, difficulty maintaining body temperature, absence of tears, and breath holding. During childhood, affected individuals may experience a variety of autonomic crises, including vomiting, difficulty regulating blood pressure, and fast or irregular heart rate. Other symptoms associated with familial dysautonomia can include bed-wetting, developmental delay, curvature of the spine (scoliosis), and the inability to walk normally (gait abnormalities).
ELP1 (formerly known as IKBKAP) is the only known cause of familial dysautonomia. Test sensitivity is high in individuals of Ashkenazi Jewish descent. More than 99% of affected patients are homozygous for an intronic splice site mutation (c.2204+6T>C) that results in tissue-specific skipping of exon 20. Another less common pathogenic variant (p.Arg696Pro) has also been identified in the Ashkenazi Jewish population.
Familial dysautonomia is inherited as an autosomal recessive disorder.
Familial dysautonomia is expressed from birth. It has full penetrance, but phenotypic severity can vary.
Familial dysautonomia is found almost exclusively among individuals of Ashkenazi Jewish descent and has an incidence of 1 in 3,700 live births in this population. The carrier frequency of the c.2204+6T>C in the Ashkenazi Jewish population is approximately 1 in 30.
Infants with familial dysautonomia often present with feeding difficulties that result from poor oral coordination and difficulty swallowing. In addition, suspicion of a familial dysautonomia diagnosis should be considered in the following scenarios:
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|