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L.G. Riley et al.
tyrosylation activity as previously described.10 Apparent kinetic
sequencing panels or exome sequencing (Table 1A and 1B). The majority of these families were derived from a group of more than 200 probands with CSA referred to SSB, MDF and MMH, in which approximately 4% of cases were attributed to YARS2 variants. YARS2 variants have previously been identified in patients with myopa- thy, lactic acidosis and sideroblastic anemia 2 (MLASA2);4 however, some patients in this study did not have overt clinical features of MLASA2 other than CSA, and several individuals with biallelic variants had no phenotype what- soever. In two families, the proband had moderate sider- oblastic anemia (P8a and P9a), while a sibling with the same YARS2 genotype was not anemic and was otherwise
parameters were determined from Lineweaver-Burk plots in the
presence of 4.8 to 6.5 nM YARS2 and 0.28 to 1.12 mM native E. coli
tRNATyr (Sigma, St. Louis, MO, USA). Experimental errors on k cat
and Km varied at most by 20%. Numerical values are averages of at least two independent experiments.
Results
Phenotypic spectrum
Eleven probands with CSA were identified with poten- tially pathogenic YARS2 variants by targeted gene
Table 1A. Clinical data.
ParticipantID P1 P2a P2b P3 P4 P5 P6
YARS2 variant 1 (NM_001040436.2) YARS2 variant 2
Year of birth Gender Ethnicity
Consanguinity
Age at presentation Sideroblastic anemia
c.156C>G c.156C>G c.156C>G c.156C>G c.181C>G p.(Phe52Leu) p.(Phe52Leu) p.(Phe52Leu) p.(Phe52Leu) p.(Leu61Val) c.156C>G c.156C>G c.156C>G c.156C>G c.181C>G
c.585G>A p.(Met195Ile) c.1165_1166insG
c.572G>T p.(Gly191Val) c.590_625del
p.(Phe52Leu) p.(Phe52Leu) p.(Phe52Leu) p.(Phe52Leu) p.(Leu61Val) p.(Leu389Cysfs*6) p.(Thr197_Leu208del)
1988 Female Lebanese/ American No
14 years Severe, transfusion dependent from 27 years
2007 2009
Male Female Lebanese Lebanese
Yes Yes 6 years 4 years Severe, Mild
transfusion dependent from 6 years
2007
Male Lebanese
No
9 years Moderate
1986
Male Caucasian/ Dutch Yes
19 years Severe, transfusion dependent intermittently from 20 years 6.6
81
ND
2001 Female Caucasian/ American No
2 years Severe, transfusion dependent intermittently from 2 years 3
82.6 0.0175
1998 Female African American No
20 months
Severe,
transfusion dependent from 20 months
Hemoglobin, g/dL
MCV, fL
Abs Retic, M/mL
Retic,% 3.1 1 2.9 2 1.1 1.7 2.3
9.9 84.5 0.101
10.5 11.5 111 102 0.035 0.13
9.5 92.4 0.132
2 101 0.016
WBC x109/L
ANC x109/L
Platelets x109/L
RS, % of BM erythroblasts Transferrin saturation, % Ferritin, ng/mL
Chelation (year started) Lactic acidosis
Myopathy
Other clinical
features
Vital status
2.41 780 294
10
60 (2002) 34.4 (2002) No
Severe
9.1 mmol/L Severe Sinus tachycardia,
4.35 2960 195 ND
97 (2016) 825 (2016) Yes (2016) ND
None
Atrial
6.6 3480 305 ND
80 (2016) 296 (2016) Yes (2017) ND
None
None
5.2 2012 216 30 45 61 No
Severe
9.5 mmol/L Mild Diarrhea,
5.4
ND
374
56
90 (2014) 683 (2014) Yes (2012) Exercise induced only None Successful
3.63 617 163
ND
53
93
Yes (2011) Premortem only
Mild
Mild
cardiomyopathy
Deceased at 12 y
6.2 861-2070 324 >15
91 (2000) 256 (2000) Yes (2004) Mild
None
Thrombocytopenia,
intermittent neutropenia
Alive
septal pericardial effusion, defect
hepatosplenomegaly stemcell transplant at 28 years
neutropenia thrombocytopenia, primary ovarian failure
Deceased at 28 y Alive
Alive Alive
Alive
MCV: mean corpuscular volume; retic: reticulocytes; WBC: white blood cell count; ANC: absolute neutrophil count; RS: ringed sideroblasts; BM: bone marrow; ND: not deter- mined; y: years.
2010
haematologica | 2018; 103(12)