Table 1. Summary of Molecular Genetic Testing Used in Hyperekplexia

Gene SymbolProportion of HPX Attributed to Mutations in This Gene 1 Test MethodMutations Detected
GLRA1Familial: ~80% 2
Simplex: see footnote 3
Sequence analysisSequence variants 4, 5
6 persons 3 Deletion / duplication analysis 6Deletion of exons 1-6 and novel deletions 7, 8
SLC6A58 persons 3 Sequence analysisSequence variants 4
Deletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9
GLRB1 person 3 Sequence analysisSequence variants 4
Deletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9
GPHN1 person 3 Sequence analysisSequence variants 4
ARHGEF91 person 3Sequence analysisSequence variants 4, 10, 11
Deletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9

1. Based on more than 40 unrelated affected individuals

2. The mutation detection frequency for GLRA1 in familial hyperekplexia is high as befits a channelopathy disorder with highly penetrant mutations. The exact number is unknown, but in individuals with HPX and a first-degree family member with HPX, the mutation detection frequency is around 80% [author, personal experience/unpublished data].

3. The mutation detection frequency for all genes among individuals without a family history of HPX averages about 20% overall [Vergouwe et al 1997, Milani et al 1998, Rees et al 2001] and mainly involves compound heterozygotes or homozygotes from consanguineous relationships.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

5. Missense and nonsense mutations have been identified in autosomal dominant and autosomal recessive HPX.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Heterozygous carriers of the GLRA1 exon 1-6 deletion cannot be detected by PCR. Detection requires deletion/duplication analysis. Lack of PCR amplification of exons 1-6 implies presence of a homozygous deletion; confirmation may require deletion/duplication analysis.

8. An individual with autosomal recessive HPX and homozygous deletion of GLRA1 exons 1-6 was identified [Brune et al 1996]. Subsequently, this homozygous deletion was found in several Turkish individuals [Sirén et al 2006].

9. No deletions or duplications of GLRB, ARHGEF9, or SLC6A5 have been reported to cause hyperekplexia. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

10. Identifies a mutation in exon 2 reported by Harvey et al [2004] as well as other as-yet unreported sequence variants

11. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

From: Hyperekplexia

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