Hermansky-Pudlak Syndrome: HPS4 Gene Sequencing

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Condition Description

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive, multisystemic disorder.  The main clinical features of HPS include oculocutaneous albinism which presents as hypopigmentation of the skin and hair; reduced iris and retinal pigments; foveal hypoplasia; nystagmus; and increased crossing of optic fibers; bleeding diathesis due to a platelet storage pool deficiency; and deposition of lysosomal ceroid, which may cause pulmonary fibrosis (onset in the early thirties), granulomatous colitis (severe presentation in ~ 15% of all cases) and cardiomyopathy in some cases.  The clinical features of HPS are caused by the disruption of lysosome-related organelles in different tissue types.  The incidence of HPS is approximately 1 in 500,000-1,000,000.  HPS has an increased incidence, of up to 1 in 1800, in Puerto Rico. Locus heterogeneity has been associated with HPS and nine causative genes (HPS1-HPS9) have been identified to date. Pathogenic variants in the HPS4 (22q12.1) gene, account for approximately 12% of all cases in non-Puerto Rican populations.

References:  
  • GeneReviews
  • Wei & Li (2013). Pigm Cell Melanoma R, 26:176-192
  • OMIM #614073:  HPS
  • OMIM #606682:  HPS4 gene

Genes (1)

Indications

This test is indicated for:
 
  • Confirmation of a clinical diagnosis of HPS.
  • Carrier testing in adults with a family history of HPS.

Methodology

PCR amplification of 13 exons contained in the HPS4 gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.

Detection

Clinical Sensitivity: Sequencing can detect approximately 12% of cases in the non-Puerto Rican population. Pathogenic variants in the promoter region, some pathogenic variants in the introns and other regulatory element pathogenic variants 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 clinical and/or biochemical phenotype.
Analytical Sensitivity: ~99%

Specimen Requirements

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: Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.

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 HPS4 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.

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