Ordering
  • Test code: 06204
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
Billing
 

Invitae Hereditary Hyperekplexia Panel

Test description

The Invitae Hereditary Hyperekplexia (HKPX) panel analyzes 6 genes associated with HKPX, a disorder characterized by generalized stiffness after birth that typically normalizes within the first few years of life, along with an excessive startle reflex followed by generalized stiffness. This panel may be appropriate for individuals with signs and symptoms of HKPX. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provides accurate risk assessment and carrier status of at-risk relatives.

Order test

Primary panel (6 genes)

ARHGEF9 CLPB GLRA1 GLRB GPHN SLC6A5

Gene Disorder
ARHGEF9 early infantile epileptic encephalopathy 8 (EIEE8) / hyperekplexia
CLPB 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN)
GLRA1 HKPX1
GLRB HKPX2
GPHN molybdenum cofactor deficiency
SLC6A5 HKPX3

Hereditary hyperekplexia (HKPX) is characterized by a constellation of three cardinal features: generalized stiffness that occurs immediately after birth and typically normalizes during the first few years of life, an excessive startle reflex to unexpected stimuli (specifically auditory stimuli), and short-term stiffness following excessive startle responses, during which time voluntary movements are virtually impossible. Individuals are conscious during these episodes. Frequency of startle responses may depend on environmental factors such as stress and fatigue.

Other variable features may include periodic limb movements during sleep, myoclonus that occurs when falling asleep, an exaggerated head-retraction reflex, mild intellectual disability, and hernias. Tonic neonatal cyanotic attacks have been reported, and may be associated with sudden infant death in rare cases, though these attacks often resolve during infancy.

HKPX is typically treated with clonazepam, which has been shown to be most effective in reducing stiffness in the neonatal period and reducing stiffness related to excessive startle reflex. Clonazepam may also help to prevent symptoms of HKPX.

The GPHN and ARGHEF9 genes are associated with syndromic forms of HKPX. Infants with Molybdenum cofactor deficiency present with additional features including intractable seizures, brain atrophy, cerebral edema, dysmorphic facies, and severe developmental delays. The median survival time is approximately 36 months of age. Individuals with EIEE8 may present with severe epilepsy and intellectual disability, along with features of HKPX.

The CLPB gene is associated with MEGCANN, a neurological syndrome which sometimes presents in the neonatal period with hyperekplexia. Individuals with MEGCANN also typically have severe intellectual disability, brain atrophy, movement disorders, and bilateral cataracts.

Pathogenic variants in GLRA1 account for approximately 80% of HKPX, and pathogenic variants in SLC6A5 accounts for less than 5% of HKPX. Pathogenic variants in the other HKPX-related genes are each estimated to account for a very small proportion of individuals with HKPX.

EIEE8 is inherited in an X-linked pattern, HKPX2, MOCODC, and MEGCANN are inherited in an autosomal recessive pattern, and HKPX1 and HKPX3 can each be inherited in an autosomal dominant or recessive pattern.

HKPX has been identified in more than 70 families, and in individuals of many different ethnic backgrounds.

This test is appropriate for any individual with clinical features consistent with HKPX.

  1. Rees, MI, et al. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum. Mol. Genet. 2002; 11(7):853-60. PMID: 11929858
  2. Rees, MI, et al. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. J. Biol. Chem. 2003; 278(27):24688-96. PMID: 12684523
  3. Harvey, K, et al. The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J. Neurosci. 2004; 24(25):5816-26. PMID: 15215304
  4. Rivera, S, et al. Congenital hyperekplexia: five sporadic cases. Eur. J. Pediatr. 2006; 165(2):104-7. PMID: 16211400
  5. Macaya, A, et al. Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. Neuropediatrics. 2005; 36(6):389-94. PMID: 16429380
  6. Bakker, MJ, et al. Startle syndromes. Lancet Neurol. 2006; 5(6):513-24. PMID: 16713923
  7. Rees, MI, et al. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat. Genet. 2006; 38(7):801-6. PMID: 16751771
  8. Tijssen, MAJ, Rees, MI. Hyperekplexia. 2007 Jul 31. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301437
  9. Carta, E, et al. Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease. J. Biol. Chem. 2012; 287(34):28975-85. PMID: 22700964
  10. Wortmann, SB, et al. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am. J. Hum. Genet. 2015; 96(2):245-57. PMID: 25597510
  11. Saunders, C, et al. CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria. Am. J. Hum. Genet. 2015; 96(2):258-65. PMID: 25597511

Assay and technical information

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
ARHGEF9 NM_015185.2; NM_001173479.1
CLPB NM_030813.5
GLRA1 NM_000171.3
GLRB NM_000824.4
GPHN NM_020806.4
SLC6A5 NM_004211.3