Family#PresentingHPOs HP:0001251, HP:0001272

FamilyNotHPOs HP:0001875, HP:0001873, HP:0001903, HP:0005518

Family#PreviousTesting Haplotype analysis by evaluation of STRP markers flanking disease causeing genes such as SCA1-19, AT, TERC, etc. (Table S1).

CountryofOrigin Germany, Ireland, North America

Family#Method1 PCR

Family#GenotypingMethod Allele-specific PCR amplification of the SAMD9L c.2640C>A variant was performed, (SNP)-based genome-wide linkage analysis

Affected 7

Unaffected 4

Segregations 6

eLOD 1.8

ProbandLabel UW-AP:IV-1, M, 18yo onset

CasePreviousTesting MVC(44[0/1]), WBC(87[0/1]), platelets(8.1[0/1])

CaseGenotypingMethod WES then confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

Case# Li-AP:II-4, F, 19 report

CasePresentingHPOs HP:0002066, HP:0000639, HP:0001903, HP:0005528, HP:0001251, HP:0001260,

HPO free text: "A bone marrow biopsy at age 14 showed hypocellularity with normal karyotype. A marrow sample obtained at age 17 failed to yield mitotic cells for cytogenetic analyses, both on direct preparation and after culture for up to 48 hr. At age 54 years, she has developed moderately severe ataxia and requires a walker to ambulate. Her mental status is normal and she has mild horizontal and vertical nystagmus, dysarthria, dysmetria, bilateral Babinski responses, and mild decreased appreciation of vibration in her toes. Brain MRI at the age of 52 years showed severe diffuse cerebellar atrophy as well as diffuse bilateral white matter signals throughout the cerebrum."

CasePreviousTesting Clinical genetic testing ruled out abnormalities in an extensive panel of dominant cerebellar ataxia genes.

CaseMethod1 Sanger

CaseGenotypingMethod Targeted Sanger sequencing of the single large coding exon of SAMD9L

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

CasePMIDs 6947857(1981)

Family#PresentingHPOs HP:0001251, HP:0001272

FamilyNotHPOs HP:0001903, HP:0004808, HP:0001876, HP:0005528

Family#PreviousTesting Studied blastogenic responses to pokeweed mitogen, phytohemagglutinin, and concanav~lin A and rate of unscheduled DNA synthesis in fibroblasts which were normal. II-5 karyotyping showed he had C-monosomy 7.

Family#Method1 Sanger Sequencing

Family#GenotypingMethod Targeted Sanger sequencing of the single large coding exon of SAMD9L

Affected 3

Unaffected 1

Segregations 2*

AddSegregationInfo

ProbandLabel Li-AP:II-4, F, 19 report

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

FamilyAddInfo Italian Mother(asymptomatic), Polish Father and 3 brothers had cerebellar ataxia/atrophy. 2 brothers died with acute mylogenous leukemia, other died with pancytopenia and hypoplastic bone marrow

FamilyPMIDs 6947857

Family#PresentingHPOs HP:0002721, HP:0001905

FamilyNotHPOs HP:0002721, HP:0002141, HP:0002863

CountryOrigin Sweden

Family#PreviousTesting Absolute lymphocyte counts and assays of cytotoxic lymphocyte phenotype and function

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES then variant confirmed with Sanger in I-3, III-1, III-2, II-4, and I-4

Affected 7

Unaffected 3

Segregations 5

eLOD 1.5

ProbandLabel F1:III-1, M, 4yo diagnosis

CasePresentingHPOs HP:0002503, HP:0000639, HP:0002317, HP:0008969, HP:0007340 (in addition to family not presenting)

HPO Free Text: congenital cytomegalovirus infection, trilineage cytopenia and MDS −7 diagnosis at the age of 4 years. Concurrent cellular immunodeficiency with decreased peripheral blood B and NK cell numbers and borderline monocyte numbers. Immunoglobulin (Ig) levels were also low (IgG, 3.36 g/L; IgA, 0.37 g/L; IgM, 0.49 g/L). MDS with −7 and −22 at 4 y of age; severely hypoplastic bone marrow diagnosed as pediatric refractory cytopenia. Hb[102-139(0/9) vs 117-153], MCV[89-95(6/6) vs 75-87], Platelets[87-128(8/9) vs 125-140], WBC[2.4-4.5(9/9) vs 5-15]

Variant NM_152703.4(SAMD9L):c.698C>A (p.Thr233Asn)

CAID CA4343828

VariantEvidence (Figure 5) 293FT cells transfected with p.Arg986Cys showed more limited cell proliferation than WT SAMD9L

FamilyAddInfo Aunt(II-1)/Mother(II-2) have NM_152703.3:c.689A>C(p.Asn230Thr), CA368201553 in cis with index's variant and have milder symptoms. Another aunt(II-4) has a NM_152703.3:c.2957G>T(p.Arg986Leu) and NM_152703.3:c.1204_1208del(p.Leu402ArgfsTer8) with cytopenias.

FamilyPMIDs 28852709

Case# F2:II-4, 18mo diagnosis, M, Finnish

CasePresentingHPOs HP:0001873, HP:0011950, HP:0001875, HP:0000639, HP:0002141, HP:0001387, HP:0002395, HP:0002863, HP:0002721, HP:0007018, HP:0001310, HP:0002172

HPO free text: "Thrombocytopenia at 2 mo followed by trilineage cytopenia at 14 mo of age. Bronchiolitis at 6 wk and varicella infection at 4 mo of age, both requiring hospitalization; recurrent otitis and laryngitis before the HSCT. MDS −7 at 18 mo of age; normal bone marrow cellularity and dysplastic megakaryocytes and clear myelodysplasia in the megakaryopoiesis." Hb[82-128(28/90) vs 117-122], MCV[73-90(82-98) vs 82-98], Platlets[37-444(32/90) vs 150-360], WBC[2.5-12.3(61-90) vs 3.4-8.2]

CasePreviousTesting Absolute lymphocyte counts and assays of cytotoxic lymphocyte phenotype and function. Hemoglobin(82-128[28/90 abnormal readings/total readings] vs 117-122 normal), Platelets(37-444[32/90] vs 150-360), WBC(2.5-12.3[61/90] vs 3.4-8.2), MCV(73-90[15/90] vs 117-122).

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES then confirmed variant with Sanger

Variant NM_152703.4(SAMD9L):c.2672T>C (p.Ile891Thr)

ClinVar 446529

VariantEvidence (Figure 5) 293FT cells transfected with p.Ile891Thr showed more limited cell proliferation than WT SAMD9L

CaseAddInfo Uniparental Disomy of WT allele in patient

CasePMIDs 28852709

Family#PresentingHPOs HP:0000639, HP:0007256, HP:0001251

FamilyNotHPOs HP:0001260, HP:0000486, HP:0001310

CountryOrigin Sweden

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod expanded pedigree confirmed to have SAMD9L variants with Sanger

Affected 5

Unaffected 9

Segregations 3*

AddSegregationInfo not to score

ProbandLabel Fam1:IV-3, Female, 38yo reported

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys), NM_152703.3:c.689A>C(p.Asn230Thr)

ClinVar 446530(c.2956), CA368201553(c.689)

FamilyAddInfo at least one member with the variant who is unaffected, but likely due to age (4yo)

FamilyPMIDs 28202457

Case# *II-4, 54yo reported

CasePresentingHPOs HP:0001310, HP:0001260, HP:0001251, HP:0000639, HP:0009072, HP:0008969, HP:0003487

CaseMethod1 WES

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

Case# Fam2:II-4, M, 7yo onset, Finnish

CasePresentingHPOs HP:0001310, HP:0001260, HP:0001251, HP:0000639, HP:0009072, HP:0008969, HP:0003487

CaseMethod1 WES

Variant NM_152703.4(SAMD9L):c.2672T>C (p.Ile891Thr)

ClinVar 446529

CaseAddInfo previously in 28202457

Case# UW-AP:III-3, 60yo reported

CasePresentingHPOs HP:0001251, HP:0001310, HP:0001260, HP:0000639, HP:0007256

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

CaseAddInfo only genotyping methods described are for extended Family 1 or in a previous study. Is this UW family also from another study?

Case# P7, 2yo report

CasePresentingHPOs HP:0005528, HP:0001873

CasePreviousTesting genes related to MDS/inherited bone marrow failure syndromes was performed in patients, negative for this patient

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

CaseAddInfo transient monosomy 7 with somatic mutation of new variant NM_152703.3:c.3951_3955del (p.Ser1317ArgfsTer21) - CA658820702

Case# P5, 7yo report

CasePresentingHPOs HP:0005528, HP:0001873

CasePreviousTesting genes related to MDS/inherited bone marrow failure syndromes was performed in patients, negative for this patient

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys)

ClinVar 446530

VariantEvidence (Figure 5) 293FT cells transfected with p.Arg986Cys showed more limited cell proliferation than WT SAMD9L in 28202457

CaseAddInfo "The HLA-identical brother of P5 was thoroughly evaluated as a potential bone marrow donor. He was clinically healthy and had a normal complete blood count, but he did not qualify as a donor because of hypocellular bone marrow with mild dysplastic features. He was also a carrier of the p.R986C mutation."

Family#PresentingHPOs HP:0000639

FamilyNotHPOs HP:0001251, HP:0001876, HP:0005528

CountryOrigin France

Family#Method1 WES

Family#Method2 Sanger

FamilyGenotypingMethod WES results confirmed with Sanger

Affected 3

Unaffected 2

Segregations 3

AddSegregationInfo family not to score

ProbandLabel UB612, M, 13mo diagnosis

CasePresentingHPOs HP:0005528, HP:0000639, HP:0001876

CaseAddInfo "Transplantation was planned but eventually cancelled because his blood cell counts improved spontaneously," possibly due to UPD.

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys)

ClinVar 446530

VariantEvidence (Figure 5) 293FT cells transfected with p.Arg986Cys showed more limited cell proliferation than WT SAMD9L in 28202457

FamilyAddInfo Monosomy 7 in IV:1, mother and aunt also recovered, likely due to UPD or revertant mosaicism