Table 9:
Pathogenic Gene Variants Associated with Hermansky-Pudlak Syndrome Types 7 through 10 (HPS-7 - HPS-10)
| # | mRNA | Amino Acid | Exon/Intron | Variant Type 1 | Reference SNP (dbSNP) 2 | Ethnic Background (age, gender) 3 | References and Footnotes |
|---|---|---|---|---|---|---|---|
| HPS-7: DTNBP1 (BLOC1S8, Dysbindin) | |||||||
| NM_032122.4 | NP_115498.2 | ||||||
| 1 | c.177G>A | p.Trp59* | Exon 4 | Nonsense | rs727502866 | Caucasian (77y, F) | (Lowe et al., 2013) 4 |
| 2 | c.307C>T | p.Gln103* | Exon 5 | Nonsense | rs104893945 |
Portuguese (48y, M), Paraguayan (6y, M) Portuguese (26y, M;56y, F) Portuguese (18y, F) Argentinian (M) |
(Li et al., 2003) (Bryan et al., 2017) 5 (Bastida et al., 2019) 5 (Bastida et al., 2019) 5 unreported 5,6 |
| 3 | c.771_774delCTCT | p.Asn257Lysfs*13 | Exon 9 | Indel | - | - (1 case) | (Lasseaux et al., 2018) 5 |
| 4 | c.1017_1020delAGAG | p.Glu340Profs*44 | Exon 10 | Indel | - | Argentinian (M) | unreported 5,6 |
| HPS-8: BLOC1S3 (Reduced Pigmentation) | |||||||
| NM_212550.4 | NP_997715.1 | ||||||
| 1 | c.131C>A | p.Ser44* | Exon 2 | Nonsense | rs281865115 | Iranian (6y, M) | (Cullinane et al., 2012) |
| 2 | c.385_403del19 | p.Ser129Glnfs*90 | Exon 2 | Indel | - | - (1 case) | (Lasseaux et al., 2018) 5 |
| 3 | c.444_467del24 | p.Gln150_Ala157del | Exon 2 | Indel | rs754841982 | - (1 case) | (Lasseaux et al., 2018) 5 |
| 4 | c.448delC | p.Gly150Argfs*75 | Exon 2 | Frameshift | rs281865116 | Pakistani (6 familial cases) | (Morgan et al., 2006) 7 |
| HPS-9: BLOC1S6 (PLDN) | |||||||
| NM_012388.3 8 | NP_036520.1 | ||||||
| 1 | c.232C>T | p.Gln78* | Exon 2 | Nonsense | rs201348482 |
Italian (17y, F), Pakistani (4y, F) Indian (9mo, M) |
(Badolato et al., 2012) 5,9 (Yousaf et al., 2016) 5 (Cullinane et al, NIH unpublished) |
| 2 | c.285_286dupTC | p.His96Leufs*22 | Exon 3 | Indel | - | Japanese (52y, F) | (Okamura et al., 2018) 5,9 |
| HPS-10: AP3D1 | |||||||
| NM_001261826.3 | NP_001248755.1 | ||||||
| 1 | c.1978delG | p.Ala660Argfs*54 | Exon 17 | Frameshift | - | 3 siblings | (Mohammed et al., 2018) 5,10 |
| 2 | c.3565_3566delGT | p.Val1189Leufs*8 | Exon 32 | Indel | rs879255646 | Turkish (3.5y, M) | (Ammann et al., 2017; Ammann et al., 2016) 5,11 |
When deletion/insertion is 1 nucleotide it is named Frameshift, when larger it is named Indel.
Reference SNP numbers for each variant as listed in dbSNP (https://www.ncbi.nlm.nih.gov/snp; searched November 2019), none of the listed SNPs in this Table has a reported allele frequency, suggesting they are rare variants.
Extracted from literature reference. Age (y, years at reporting) and gender (M, male; F, female) of each subject is included for future comparison of additional cases. ‘-‘ = unreported.
This subject also developed granulomatous colitis (Lowe et al., 2013).
The variant in this report was identified by next generation sequencing.
This DTNBP1 variant was identified by exome sequencing in one unreported male subject of Argentinian descent in the NIH HPS cohort referred by Dr. Rosenzweig, NIH Clinical Center, NIH, Bethesda, MD). This subject is compound heterozygous for c.307C>T and c.1017_1020delAGAG.
One extended Pakistani family with 6 affected HPS-8 cases homozygous for c.448delC was reported (Morgan et al., 2006).
Both BLOC1S6 pathogenic variants were reported according to transcript variant 2 (NM_012388.3) nomenclature and are listed as such in this Table to avoid confusion. A longer transcript variant (Variant 1, NM_001311255.1), appeared recently in databases, and future reports may adjust variant nomenclature.
Both the Italian and Japanese subjects had a history of recurrent leucopenia and mild thrombocytopenia, causing immunodeficiency (Badolato et al., 2012; Okamura et al., 2018). The Japanese subject developed schizophrenia in her late forties, a phenotype also associated with DTNBP1 haplotypes.
Next generation sequencing identified this rare AP3D1 frameshift variant c.1978delG homozygous in 3 siblings with seizures, developmental delay, albinism and immunodeficiency. Twin girls died before 6 days of age and their brother died at age 2 years of pneumonia and sepsis (Mohammed et al., 2018).
Next generation sequencing identified this rare AP3D1 variant c.3565_3566delGT in a proband with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing. Immunologic investigations excluded HLH in this subject. The proband died at age 3.5 years as result of septic pneumonia (Ammann et al., 2016).