Table 2.

List of 30 patients in whom only 1 heterozygous pathogenic or likely pathogenic variant was identified

Patient no.SexAge at testing, y (unless indicated otherwise)EthnicityGeneVariantZygosityPopulation frequency (gnomAD*), %Symptoms/immunology testing/family history†
S01 Female 28.3 Unknown PRF1 c.35_46del(p.Leu12_Leu15del) Heterozygous ND NA 
S02 Male 20 d Unknown PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Decreased NK cell function and perforin expression 
S03 Female 0.4 Unknown PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Symptoms of HLH 
S04 Male 7.8 African American PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Decreased perforin expression 
S05 Female 11.2 African American PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Absent NK cell function 
S06 Male 52 African American PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 HLH, lymphoma 
S07 Male 13.3 Native American PRF1 c.112G>A(p.Val38Met) Heterozygous 0.0073 Symptoms of HLH 
S08 Male 16.6 Latino-Hispanic PRF1 c.445G>A(p.Gly149Ser) Heterozygous 0.014 Symptoms of HLH 
S09 Female 9.9 Unknown PRF1 c.563C>T(p.Pro188Leu) Heterozygous 0.013 Symptoms of HLH 
S10 Male 17.8 Unknown PRF1 c.853_855del(p.Lys285del) Heterozygous 0.0057 Thrombocytopenia, absent NK cell function 
S11 Female 3.1 European-American PRF1 c.1066C>T(p.Arg356Trp) Heterozygous 0.0014 NA 
S12 Female 3 Unknown PRF1 c.1117C>T(p.Arg373Cys) Heterozygous 0.0051 Symptoms of HLH; normal NK cell function 
S13 Female 16.7 Unknown PRF1 c.1117C>T(p.Arg373Cys) Heterozygous 0.0051 Absent NK cell function 
S14 Female 12 d Middle Eastern PRF1 c.1122G>A(p.Trp374*) Heterozygous 0.0016 NA 
S15 Female 9.7 Malaysian-Chinese PRF1 c.1349C>T(p.Thr450Met) Heterozygous 0.0028 History of HLH 
S16 Female 0.5 Middle Eastern STXBP2 c.1430C>T(p.Pro477Leu) Heterozygous 0.00074 Symptoms of HLH 
S17 Female 0.5 Latino-Hispanic STXBP2 c.1717C>T(p.Pro573Ser) Heterozygous ND NA 
S18 Male 37 d European-American STXBP2 c.1717C>T(p.Pro573Ser) Heterozygous ND Absent NK cell function 
    PRF1 c.272C>T(p.Ala91Val)‡ Heterozygous 2.92 
S19 Male 14.9 Asian-American UNC13D c.118-307G>A Heterozygous ND Absent NK cell function 
S20 Male 20.3 Unknown UNC13D c.247C>T(p.Arg83*) Heterozygous 0.0004 NA 
S21 Female 62.9 European-American UNC13D c.1759C>T(p.Arg587Cys) Heterozygous 0.019 Symptoms of HLH 
S22 Female 13.1 European-American UNC13D c.2037_2038insG(p.Arg680fs) Heterozygous ND Symptoms of HLH, one sibling deceased due to HLH 
S23 Male 0.8 Middle Eastern RAB27A c.148_149delinsC(p.Arg50fs) Heterozygous ND Gray hair, suspected for GS, consanguinity 
    PRF1 c.272C>T(p.Ala91Val)‡ Heterozygous 2.92 
S24 Male 3 European-American RAB27A c.240-47_240delins20 Heterozygous ND Rash, neutropenia 
S25 Male 11.1 Indian RAB27A c.244C>T(p.Arg82Cys) Heterozygous 0.0016 Symptoms of HLH 
S26 Female 24.9 Latino-Hispanic RAB27A c.335del(p.Asn112fs) Heterozygous 0.0044 Symptoms of HLH 
S27 Male 2.1 Unknown RAB27A c.400_401del(p.Lys134fs) Heterozygous 0.0004 Abnormal brain MRI, decreased NK cell function 
S28 Male 29 European-American LYST c.465_466del(p.Asp157fs) Heterozygous ND Pancytopenia, increased ferritin level 
S29 Male 6.4 Middle Eastern LYST c.4159dup(p.Thr1387fs) Heterozygous ND Gray hair 
S30 Female 23.2 Unknown STX11 c.650T>A(p.Leu217Gln) Heterozygous 0.0004 NA 
    PRF1 c.272C>T(p.Ala91Val)‡ Heterozygous 2.92 
Patient no.SexAge at testing, y (unless indicated otherwise)EthnicityGeneVariantZygosityPopulation frequency (gnomAD*), %Symptoms/immunology testing/family history†
S01 Female 28.3 Unknown PRF1 c.35_46del(p.Leu12_Leu15del) Heterozygous ND NA 
S02 Male 20 d Unknown PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Decreased NK cell function and perforin expression 
S03 Female 0.4 Unknown PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Symptoms of HLH 
S04 Male 7.8 African American PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Decreased perforin expression 
S05 Female 11.2 African American PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 Absent NK cell function 
S06 Male 52 African American PRF1 c.50del(p.Leu17fs) Heterozygous 0.033 HLH, lymphoma 
S07 Male 13.3 Native American PRF1 c.112G>A(p.Val38Met) Heterozygous 0.0073 Symptoms of HLH 
S08 Male 16.6 Latino-Hispanic PRF1 c.445G>A(p.Gly149Ser) Heterozygous 0.014 Symptoms of HLH 
S09 Female 9.9 Unknown PRF1 c.563C>T(p.Pro188Leu) Heterozygous 0.013 Symptoms of HLH 
S10 Male 17.8 Unknown PRF1 c.853_855del(p.Lys285del) Heterozygous 0.0057 Thrombocytopenia, absent NK cell function 
S11 Female 3.1 European-American PRF1 c.1066C>T(p.Arg356Trp) Heterozygous 0.0014 NA 
S12 Female 3 Unknown PRF1 c.1117C>T(p.Arg373Cys) Heterozygous 0.0051 Symptoms of HLH; normal NK cell function 
S13 Female 16.7 Unknown PRF1 c.1117C>T(p.Arg373Cys) Heterozygous 0.0051 Absent NK cell function 
S14 Female 12 d Middle Eastern PRF1 c.1122G>A(p.Trp374*) Heterozygous 0.0016 NA 
S15 Female 9.7 Malaysian-Chinese PRF1 c.1349C>T(p.Thr450Met) Heterozygous 0.0028 History of HLH 
S16 Female 0.5 Middle Eastern STXBP2 c.1430C>T(p.Pro477Leu) Heterozygous 0.00074 Symptoms of HLH 
S17 Female 0.5 Latino-Hispanic STXBP2 c.1717C>T(p.Pro573Ser) Heterozygous ND NA 
S18 Male 37 d European-American STXBP2 c.1717C>T(p.Pro573Ser) Heterozygous ND Absent NK cell function 
    PRF1 c.272C>T(p.Ala91Val)‡ Heterozygous 2.92 
S19 Male 14.9 Asian-American UNC13D c.118-307G>A Heterozygous ND Absent NK cell function 
S20 Male 20.3 Unknown UNC13D c.247C>T(p.Arg83*) Heterozygous 0.0004 NA 
S21 Female 62.9 European-American UNC13D c.1759C>T(p.Arg587Cys) Heterozygous 0.019 Symptoms of HLH 
S22 Female 13.1 European-American UNC13D c.2037_2038insG(p.Arg680fs) Heterozygous ND Symptoms of HLH, one sibling deceased due to HLH 
S23 Male 0.8 Middle Eastern RAB27A c.148_149delinsC(p.Arg50fs) Heterozygous ND Gray hair, suspected for GS, consanguinity 
    PRF1 c.272C>T(p.Ala91Val)‡ Heterozygous 2.92 
S24 Male 3 European-American RAB27A c.240-47_240delins20 Heterozygous ND Rash, neutropenia 
S25 Male 11.1 Indian RAB27A c.244C>T(p.Arg82Cys) Heterozygous 0.0016 Symptoms of HLH 
S26 Female 24.9 Latino-Hispanic RAB27A c.335del(p.Asn112fs) Heterozygous 0.0044 Symptoms of HLH 
S27 Male 2.1 Unknown RAB27A c.400_401del(p.Lys134fs) Heterozygous 0.0004 Abnormal brain MRI, decreased NK cell function 
S28 Male 29 European-American LYST c.465_466del(p.Asp157fs) Heterozygous ND Pancytopenia, increased ferritin level 
S29 Male 6.4 Middle Eastern LYST c.4159dup(p.Thr1387fs) Heterozygous ND Gray hair 
S30 Female 23.2 Unknown STX11 c.650T>A(p.Leu217Gln) Heterozygous 0.0004 NA 
    PRF1 c.272C>T(p.Ala91Val)‡ Heterozygous 2.92 
*

gnomAD v2.1.1 total population frequency.

†

HLH hemophagocytic lymphohistiocytosis, symptoms of HLH reported included any or all of the following “fever, hepatosplenomegaly, anemia/cytopenias, neutropenia/leukopenia, elevated ferritin/triglycerides, and/or decreased fibrinogen.”

‡

According to the ACMG guideline, c.272C>T(p.Ala91Val) in PRF1 was classified as a variant of unknown significance.

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