XLMR 30: PAK3 Gene Sequencing

Create a PDF of this page

Condition Description

Intellectual disability (ID) is a nonprogressive cognitive impairment affecting 1-3% of the Western population. It is estimated that up to 50% of moderate-severe cases have genetic causes and approximately 10% are due to X-linked intellectual disability disorders (XLID). XLID can be syndromic or nonsyndromic and is observed in all ethnic groups. More than 100 XLID syndromes have been described in the literature to date. Fragile X is the most common XLID syndrome (~1 in 4000 males) while others can be quite rare with only a few patients reported in the literature. Males can have moderate to severe intellectual disability depending on the syndrome, and carrier females can also be affected, but typically have milder clinical symptoms.

Mutations in the PAK3 gene have been identified in five families with XLID.  Three of the mutations are missense mutations (Bienvenu et al. 2000; Gedeon et al. 2003; Peippo et al. 2007), one is a nonsense mutation (Allen et al. 1998), and one is a splice-site mutation (Rejeb et al. 2008).  Common features seen in affected males for these five families include microcephaly, oral motor dysfunction with persistent drooling and inarticulate speech, and behavioral and psychiatric symptoms.  Female carriers are often asymptomatic; however, they could show borderline to mild intellectual disability.

References:
•    OMIM #300558: XLMR 30
•    OMIM #300142: PAK3 gene
•    Rejeb et al. (2008) Eur J Hum Genet, 16:1358-1363.
•    Bienvenu et al. (2000) Am J Med Genet, 93:294-298.
•    Gedeon et al. (2003) Am J Med Genet A, 120:509-517.
•    Peippo et al. (2007) Am J Med Genet A, 143:2406-2416.
•    Allen et al. (1998) Nat Genet, 20:25-30.

Genes (1)

Indications

This test is indicated for:

  • Confirmation of a clinical diagnosis of XLMR 30.
  • Carrier testing in adults with a family history of XLMR 30.

Methodology

Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient's genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not meant to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient's gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.

Detection

Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Submit only 1 of the following specimen types

Preferred specimen type: Whole Blood

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

Special Instructions

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of Emory Genetics Laboratory, please submit a copy of the sequencing report with the test requisition.
  • Deletion/duplication analysis of the PAK3 gene by CGH array is available for those individuals in whom sequence analysis is negative.
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available only for known familial mutations to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.
  • X-Linked Intellectual Disability panels are available for 30, 60, and 90 genes.

How to Order