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Heterogeneity in CAMT-MPL
Table 2D. Missense mutations in congenital amegakaryocytic thrombocytopenia patients
CDS
c.23T>G
c.304C>T
c.305G>A
c.305G>C
c.311T>C
c.404C>G
c.407C>A
c.407C>T
c.407C>G
c.460T>C
c.506T>A
c.769C>T
c.770G>T
c.805T>C
c.823C>A
c.883G>C
c.944T>G
c.1180C>T
c.1305G>C
c.1361G>C
c.1390A>G
Exon protein
E1 p.Met8Arg E3 p.Arg102Cys E3 p.Arg102His E3 p.Arg102Pro E3 p.Phe104Ser E4 p.Pro135Arg E4 p.Pro136His E4 p.Pro136Leu E4 p.Pro136Arg E4 p.Trp154Arg E4 p.Leu169His E5 p.Arg257Cys E5 p.Arg257Leu E5 p.Trp269Arg E5 p.Pro275Thr E6 p.Asp295Tyr E6 p.Phe315Cys E8 p.Pro394Ser E8 p.Trp435Cys E9 p.Arg454Pro E9 p.Arg464Gly
MutationTaster
polymorphism / 0.963
disease causing / 1.000
disease causing /0.983
disease causing / 0.995
disease causing / 0.975
disease causing / 0.995
disease causing / 0.991
disease causing / 1.000
disease causing / 0.995
disease causing / 0.984
disease causing / 0.903
disease causing / 1.000
disease causing /1.000
disease causing / 0.994
disease causing / 0.985
disease causing / 0.998
disease causing / 0.999
disease causing / 0.981
disease causing / 1.000
polymorphism / 1.000
polymorphism / 0.993
disease causing / 0.807
disease causing / 0.981
polymorphism / 0.986
PROVEAN
polymorphism / 0.963 disease causing / 1.000 disease causing /0.983 disease causing / 0.995 disease causing / 0.975 disease causing / 0.995 disease causing / 0.991 disease causing / 1.000 disease causing / 0.995 disease causing / 0.984 disease causing / 0.903 disease causing / 1.000 disease causing /1.000 disease causing / 0.994 disease causing / 0.985 disease causing / 0.998 disease causing / 0.999 disease causing / 0.981 disease causing / 1.000 polymorphism / 1.000 polymorphism / 0.993 disease causing / 0.807 disease causing / 0.981 polymorphism / 0.986
SIFT
damag. /0.004 toler. / 0.064 toler. / 0.291 toler. / 0.082 damag. / 0.001 damag. / 0.000 damag. / 0.000 damag. / 0.000 damag. / 0.000 damag. / 0.000 damag. / 0.001 damag. / 0.002 damag. / 0.005 damag. / 0.000 damag. / 0.008 damag. / 0.002 damag. / 0.003 damag. / 0.004 damag. / 0.000 toler. / 0.391 damag. / 0.006 damag. / 0.002 damag. / 0.004 damag. / 0.000
incidence
ho: n=1; het: n=0 ho: n=1; het: n=1 ho: n=0; het: n=1 ho: n=4; het: n=5 ho: n=0; het: n=1 ho: n=0; het: n=1 ho: n=1; het: n=0 ho: n=0; het: n=2 ho: n=0; het: n=1 ho: n=2; het: n=0 ho: n=1; het: n=1 ho: n=0; het: n=2 ho: n=1; het: n=0 ho: n=1; het: n=0 ho: n=0; het: n=1 ho: n=2; het: n=0 ho: n=0; het: n=1 ho: n=2; het: n=0 ho: n=2; het: n=0 ho: n=1; het: n=0 ho: n=1; het: n=0 ho: n=1; het: n=0 ho: n=1; het: n=0 ho: n=0; het: n=1
c.1571T>G E11 p.Leu524Arg
c.1742C>T E12 p.Pro581Leu
c.1781T>G E12 p.Leu594Trp
CDS: coding DNA sequence; ho: homozygous individuals: het: heterozygous individuals.
THPO values, despite complete MPL deficiency, could be due to recent platelet transfusions or duration and condi- tion of sample shipment.
Clinical phenotype
Inheritance
Twenty-nine (52%) of the patients in our cohort had consanguineous parents and were homozygous for the particular MPL mutation. Homozygous mutations in patients with no evidence for parental consanguinity (n=9) were mainly affected from the most prevalent mutation c.305G>C (n=4) or from mutations with a high- er prevalence in a specific region (c.506T>A, see above) or ethnic group (c.79+2T>A).28
Some families had more than one affected patient: CAMT009 + CAMT031, CAMT018 + CAMT019 + CAMT036 + CAMT180, and CAMT133 + CAMT140 each belongs to large kindreds with a high degree of con- sanguinity. Other cases of CAMT, aplastic anemia or not otherwise specified “bleeding disease” are reported in these kindreds. CAMT101 and CAMT102 as well as CAMT130 and CAMT137 are siblings from non-consan- guineous families. CAMT083 is the fetus of a second pregnancy of the mother of CAMT052. Bone marrow analysis during autopsy revealed normal cellularity with absent megakaryocytes.
Pregnancies, deliveries, symptoms at birth
Pregnancies and deliveries were unremarkable in the majority of the cases. Median gestational age was 40
weeks (n=34, range, 31-42 weeks of gestation [wGA]), mean birth weight 3,080 g (n=25, range, 1,545-4,280 g).
Intracranial bleeding in utero was detected in some patients (seven of 46),† retrospectively in four of seven. Two children were delivered by cesarean section due to diagnosis of cerebral hemorrhage: CAMT013 with a hydrops fetalis due to Rhesus incompatibility (wGA 31) and CAMT123 after an intracranial bleeding in wGA 28 (wGA 38). Pregnancy of CAMT083 was terminated in wGA 22 because of very poor prognosis after intracranial bleeding. There were three other cesarean sections for reasons only related to the mother.
We found a significant female predominance in our cohort (62.5%, P<0.05 according to χ2-test).2 This is in contrast to most of the other IBMFS in which boys are affected more often.29 We have no information about the number and sex ratio of miscarriages in the patients’ fam- ilies as a possible hint for the female predominance.
Thrombocytopenia, bleeding
Although thrombocytopenia at birth has been classified as one of the diagnostic hallmarks of CAMT so far, 13 of 52† patients in this study with available information showed no signs of thrombocytopenia at birth and no blood counts were taken. Twelve of 13 patients had mutations allowing for a residual MPL activity. In the remaining patients (39 of 52)† thrombocytopenia was detected at birth (n=38) or at termination of pregnancy (n=1). Available data for platelet counts at birth ranged from 1-36 G/L (median 15 G/L, n=30). Petechiae or pur-
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