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 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).
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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|