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D.M. Gianferante et al.
Table 1. Clinical phenotypes of cases with RPL35A large deletion versus all other RPL35A pathogenic variants.
Cases Cases with
RPL35A
large deletion
Cases with P all other
RPL35A
variants
23 - 13/10 0.14
Demographic information
Total cases
Male/female
Age of presentation in months, median (range)
Hematologic and immune phenotypes1
Anemia
Requiring treatment HCT Steroid-resistant2
Thrombocytopenia Neutropenia
Requiring treatment3 Immunodeficiency Recurrent infection
Congenital abnormalities
Craniofacial
Microcephaly4 Skeletal/limb5
Cardiac
Urogenital
Short stature6
Any congenital abnormality7 ≥3 abnormalities
Other phenotypes
Chronic GI problem
Intellectual disability
45 22 20/25 7/15
- 0 (0-12) 44 22
2 (0-60)
0.04*
22 1
42 22
7 4 3 0.70
26 18 8 0.0023 4 1 3 0.61 33 21 12 0.0017 10 9 1 0.004 9 8 1 0.01 15 11 4 0.03
12 11 1 0.0006 10 7 3 0.17 11 9 2 0.02 10 7 3 0.17 10 5 5 1 23 11 12 1 26 16 10 0.07 13 11 2 0.003
9 9 0 0.0006 15 13 2 0.0004
20 0.23
All cases meeting criteria for sufficient phenotypic information were included (n=45).Large deletion was defined as entire RPL35A gene deleted.All other pathogenic variants included missense, nonsense, small frameshift, splice, and inframe deletions. A positive finding was counted as present, and a clinical finding marked absent or not stated was considered absent. P-value based upon Fisher exact test and one was Student t-test (*). Statistically significant P-values after Bonferroni correction are in bold (P<2.4x10-3). Treatment for anemia included steroids,chronic transfusion,erythropoietin,and hematopoietic stem cell transplant (HCT). 1Standard criteria for defining cytopenia and immun- odeficiency were used (see also Online Supplementary Table S2):31 neutropenia: absolute neutrophil count <1.5x109/L; thrombocytopenia: platelet count <150x109/L; anemia: hemoglobin <2 standard deviation below the mean for the normal population based on age and sex. 2Steroid resistant and red blood cell transfusion-dependent. 3Treatment for neutropenia: eight cases had documentation of granulocyte-colony stimulating factor use; neutropenia treatment was not specified in two cases. 4Head circumference <5th per- centile for age and sex.5Abormalities of skeleton,ribs,upper and lower extremity. 6<10th percentile for height based on age and sex.7Includes phenotypes noted in the table plus anal atresia, pyloric stenosis, presacral dimple in one case each and inguinal hernia in two cases. GI: gastrointestinal.
(absolute neutrophil count <0.5x109/L) required treatment for neutropenia compared with patients with other patho- genic variants (n=9 vs. n=1; P=0.004). Treatment of neu- tropenia included eight cases with documented use of granulocyte-colony stimulating factor (GCSF) and treat- ment not specified in two cases. Bone marrow findings were available only in nine patients with large deletions and three with other pathogenic variants. Patients with large deletion and severe neutropenia (n=7) appeared to have both myeloid and erythroid hypoplasia while those with no neutropenia had mainly erythroid hypoplasia (5 of 7 vs. 0 of 3; P=0.06).
Cases with large deletions involving RPL35A were more likely to have an immune system abnormality compared with other pathogenic variants, including an immunodefi- ciency diagnosis (n=8 vs. n=1; P=0.01) with low immunoglobulins, low numbers of lymphocyte subsets, or poor response to childhood vaccination, and treatment with intravenous immunoglobulins. Recurrent severe infections requiring hospitalization and treatment with systemic antimicrobials were also reported more common- ly in cases with large deletions (n=11 vs. n=4; P=0.03). It is noteworthy that all cases with large deletion with recur- rent infections or immune system abnormalities (12 unique cases) were also neutropenic.
There were six cases with loss of function (LOF) variants (splice site=3, nonsense=1, frameshift=2) among patients with other pathogenic variants in RPL35A. Univariate analysis comparing these six cases with the 19 cases with missense or inframe deletions showed an earlier age for the diagnosis of anemia in cases with LOF variants (P=0.02) but no association with neutropenia or immunodeficiency. Only one patient (frameshift variant) had severe neutrope- nia that was managed with GCSF, and one (splice site defect) had neutropenia and immunodeficiency treated with immunoglobulins.
Fifty-eight percent (n=26) of the cohort had at least one congenital abnormality involving craniofacial, skeletal and/or limb, cardiac, renal, genital abnormalities, or micro- cephaly (Table 1). The abnormalities described in each individual case are listed in Online Supplementary Table S4. Craniofacial abnormalities were significantly more fre- quent in cases with RPL35A large deletions compared with other pathogenic variants (n=11 vs. n=1; P=0.0006). Cases with large deletions were also more likely to have skeletal/limb abnormalities (n=9 vs. n=2; P=0.02) as well as three or more abnormalities (n=11 vs. n=2; P=0.003). Short stature, a common feature of DBA, was identified in approximately 50% of cases in each group and there was no difference in the use of steroids in
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