Table 1.

Summary of Molecular Genetic Testing Used in HPS

Gene 1
(HPS Subtype)
Proportion of HPS Attributed to Mutation of This GeneTest Method
Puerto RicanNon-Puerto Rican
~74% 2, 30%Targeted mutation analysis 4
~ 1% 343% 5Sequence analysis 6
0%~1% 7Deletion/duplication analysis 8
0%~10% 9Sequence analysis 6
~1% 10Deletion/duplication analysis 8
0%~13% 11Sequence analysis 6
25% 120%Deletion/duplication analysis 8
0%~12% 13Sequence analysis 6
0%~9% 14Sequence analysis 6
0%~7% 15Sequence analysis 6
<1% 16Deletion/duplication analysis 8
0%~1% 17Sequence analysis 6
0%1% 18Sequence analysis 6
0%1% 19Sequence analysis 6
Deletion/duplication analysis 8

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Homozygosity for the c.1470_1486dup CCAGCAGGGGAGGCCC (16-bp duplication) is found in approximately 74% of all affected individuals of Puerto Rican ancestry [Santiago Borrero et al 2006] and in most affected individuals from northwestern Puerto Rico [Oh et al 1996, Huizing et al 2008]. To date, the c.1470_1486dup CCAGCAGGGGAGGCCC (16-bp duplication) has been found exclusively in affected individuals of Puerto Rican ancestry.


Three Puerto Rican individuals with HPS-1 were compound heterozygotes for the 16-bp duplication and a second HPS1 pathogenic variant [Carmona-Rivera et al 2011b].


Targeted mutation analysis is typically for c.1470_1486dup CCAGCAGGGGAGGCCC (16-bp duplication). Note: Pathogenic variants included in a panel may vary by laboratory.


HPS1 is mutated in approximately 45% of affected non-Puerto Ricans, including Japanese, Indian, Swiss, and African Americans [Oh et al 1996, Oh et al 1998, Shotelersuk & Gahl 1998, Shotelersuk et al 1998, Oetting & King 1999, Hermos et al 2002, Huizing & Gahl 2002, Ito et al 2005, Merideth et al 2009, Vincent et al 2009]. Homozygotes as well as compound heterozygotes for HPS1 pathogenic variants have been identified. Several non-Puerto Rican Hispanic individuals with HPS1 pathogenic variants have been reported [Carmona-Rivera et al 2011a].


Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


A ~14k insertion/deletion has been reported [Griffin et al 2005].


Testing that identifies exonic or whole-gene deletions/duplications not 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.


Pathogenic variants in AP3B1 have been identified in at least 13 individuals: two adult brothers [Dell'Angelica et al 1999], a boy age six years [Huizing et al 2002], another child [Clark et al 2003], two cousins with consanguineous Turkish parents [Jung et al 2006], two Italian sibs [Fontana et al 2006], a child originally diagnosed with Griscelli syndrome [Enders et al 2006], three unrelated individuals with typical findings of HPS-2 [Chiang et al 2010, Wenham et al 2010], and a Lebanese girl with consanguineous parents harboring a homozygous chromosomal inversion within the AP3B1 gene [Jones et al 2013] .


Deletions of 8 kb [Jung et al 2006] and ~0.6 kb [Wenham et al 2010] have been reported, as well as a chromosome 5 inversion with a breakpoint in AP3B1 [Jones et al 2013].


Sequence analysis of individuals known to have HPS is expected to identify pathogenic variants in HPS3 ~15% of the time. In addition to novel variants, sequence analysis will identify individuals with HPS who are of Ashkenazi Jewish background with the c.1303+1G>A splice site variant [Huizing et al 2001a]. Of six individuals with this pathogenic variant, four were homozygotes and two were compound heterozygotes.


Homozygosity for g.339_4260del3904, (also referred to as the 3.9-kb deletion) has been identified in affected individuals of Puerto Rican ancestry only [Anikster et al 2001]. Newborn screening of 12% of the Puerto Rican population detected two homozygotes and 73 heterozygotes [Torres-Serrant et al 2010].


Pathogenic variants in HPS4 have been reported in at least 17 affected individuals [Suzuki et al 2002, Anderson et al 2003, Jones et al 2012], including a Sri Lankan [Bachli et al 2004] and a Uruguayan [Carmona-Rivera et al 2011a].


Pathogenic variants in HPS5 have been found in at least nine individuals, including a Turkish boy age three years [Zhang et al 2003], sisters of Swiss extraction age 43 and 51 years [Huizing et al 2004], a woman of English and Irish background age 21 years [Huizing et al 2004], a boy of English, Irish, Dutch, and Swedish background age ten years [Huizing et al 2004], a Turkish woman age 38 years [Korswagen et al 2008], a Mexican boy age eight months [Carmona-Rivera et al 2011a], a Cuban-Venezuelan boy age three years [Carmona-Rivera et al 2011a], and a male age 92 years, the oldest individual with HPS documented in the literature [Ringeisen et al 2013].


Six individuals with ten different pathogenic variants in HPS6 have been reported [Zhang et al 2003, Huizing et al 2009, Summers & Schimmenti 2014], in addition to an Israeli Bedouin family with a homozygous founder frameshift variant [Schreyer-Shafir et al 2006].


One large ~20-kb deletion has been identified in one subject with HPS-6 [Huizing et al 2009].


About 1% of individuals with HPS have HPS-7, caused by pathogenic variants in DTNBP1. Homozygous nonsense variants in DTNBP1 have been reported in two subjects, a Portuguese woman age 48 years [Li et al 2003] and a 77 year-old woman of northern European background [Lowe et al 2013].


A family in Britain was identified with a homozygous frameshift variant in BLOC1S3 [Morgan et al 2006], and an Iranian boy age six years with a homozygous nonsense variant has been described [Cullinane et al 2012].


A homozygous nonsense variant in BLOC1S6 was identified in a male of Indian descent age nine months [Cullinane et al 2011] and in an Italian female age 17 years [Badolato et al 2012].

From: Hermansky-Pudlak Syndrome

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