Case2: 6-month-old Male, China

DiseaseAssertion: Hemophilia B (Factor IX-deficient)

FamilyInfo: Mother and maternal grandmother are HB carriers due to a novel mutation in intron 3. Pedigree shown in Figure 1.

ParentalTesting: The F9 exons were amplified (RT-PCR) and exons 1 to 8 of the F9 gene were analyzed with the ABI 3130 Genetic Analyzer, Sequenced intron 3 of the F9 gene

CasePresentingHPOs: HP:0011858 (Reduced factor IX activity)

CaseHPOFreeRext: FIX:C 1%, Pelioma, Cyanotic bumps, Subcutaneous bleeding, knee swelling from crawling

CasePreviousTesting: Prenatal testing at 20 weeks

Gene: F9

Variant: NM_000133.3(F9):c.278-3A>G

ClinVar: 92225 https://www.ncbi.nlm.nih.gov/clinvar/variation/92225/#id_first

CAID: CA285284

gnomAD: Not Reported

Case#: 12 year old male

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: Mother was a carrier. Maternal uncle has the same hemizygous mutation

ParentalTesting: Family Pedigree reveals that the mother was a carrier of the variant identified in the proband

CasePresentingHPOs: HP:0011858, HP:0030839

CaseHPOFreeText: FIX:C = 1%, proband had a history of soft tissue hemorrhages since 7 years of age

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Direct nucleotide sequencing was completed

Gene: F9

Variant: NM_000133.3:c.157G>C

LegacyVariant:

ClinVar: No

CAID: CA414435729

gnomAD:

Case#: Riegelsberg (male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Mother carries only the G-to-A transition (age at conception: 30 y/o). Origin of variant cannot be proved, since maternal grandparents were deceased at time of report.

ParentalTesting: Mother carries only the G-to-A transition, father shows to not be affected (figure 1)

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX Coagulant %: < 1, FIX Antigen %: < 1

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.8G>A (p.Arg3His)

LegacyVariant: c.37G>A

ClinVar: 695909

CAID: CA10529706

gnomAD: Filtering AF: 0.0002304 (no homozygotes)

Case1: Female patient, 37-year-old, At age 25(pregnant) an F8 mutation was identified, Family History of Severe HA

DiseaseAssertion: Mild hemophilia A due to a family mutation and de novo mutation

FamilyInfo: Family also has the large deletion of exon 1 to 22 of the F8 gene, Son (age 10) has mild Hemophilia A

ParentalTesting: Father tested negative for any F8 mutations, Mother is an asymptomatic carrier of the familial large deletion

CasePresentingHPOs: HP:0000978 (Bruising Susceptibility), HP:0000132 (Menorrhagia)

CaseHPOFreeText: FVIII:C 7%, compounded heterozygous for the large gene deletion and c.1569G>T mild mutation

CasePreviousTesting: Molecular analysis, Sequenced the whole coding region of the F8 gene

Gene: F8

Variant: 1. F8, EX1-22DEL 2. NM_000132.3:c.1569G>T (p.Leu523=)

ClinVar: 1. 10122 https://www.ncbi.nlm.nih.gov/clinvar/variation/10122/

1. 439678 https://www.ncbi.nlm.nih.gov/clinvar/variation/439678/

gnomAD: 1. Not reported (F8, EX1-22DEL)

1. MAF for Leu523= in Latino population 0.00007293 <br /> https://gnomad.broadinstitute.org/variant/X-154185415-C-A?dataset=gnomad_r2_1

Case#: Patient UK22 (male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Mother is a carrier, two sisters (II:3, II:5) of patient UK22 were found to be carriers, niece of patient UK22 (III:4) is not a carrier

ParentalTesting: Mother is a carrier, Father was unaffected (according to pedigree; figure 1)

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (<1% of factor IX; factor IX activity of 2 IU/dl), haemarthrosis of the knee, referred at 2 y/o,

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Analysis of the essential regions of the gene; the promoter, exons, and regions containing the normal RNA processing signals only found this variant, and no other.

Gene: F9

Variant: NM_000133.4:c.50T>A (p.Ile17Asn)

LegacyVariant: c.79T>A (p.Ile-30Asn)

ClinVar: Absent

CAID: CA414434315

gnomAD: Absent/Not Reported

Case1: 3-year-old boy

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: The pathogenic mutation of F9 gene in this family was identified, Mother and Grandmother are HB carriers, Father tested negative. Pedigree shown in Figure 1.

ParentalTesting: Sequences at the mutation locus in F9 genes were analyzed by Sanger sequencing.

CasePresentingHPOs: NA

CaseHPOFreeText: Hemorrhagic spots on his skin at birth, Gingival bleeding, APTT 66.5 s, FIX:C < 1%, FVIII:C 116.8%

CasePreviousTesting: PCR amplification for coding and flanking sequences of F9 gene, PCR amplification products sequenced by Songon Biotech Co. Ltd.

Gene: F9

Variant: NM_000133.3:c.1232G>C (p.Ser411Thr)

ClinVar: NA

CAID: CA414446686

gnomAD: NA