Clinical Features
We identified 31 patients (16 males and 15 females) from 24 families with proven or presumptive biallelic SLC25A38 rare variants predicted to be functionally deleterious (Tables 1 and 2). Using Sanger or whole exome sequencing in 70 additional CSA probands without a specific genetic diagnosis, we did not identify an individual with even a singleSLC25A38 allele present in reference databases at a frequency of <0.1, nor did we find evidence of a deletion of all or part of the gene. This suggests that pathogenic SLC25A38 alleles that are occult to sequencing exons are unusual.
Two patients (13.1 and 22.4) presented with hydrops fetalis in utero . Sixteen presented in the neonatal period (<1 week of life), 10 in infancy (<12 months), and one each at 4- (4.1) and 14-years of age (14.1); the age of clinical presentation of one patient is unknown. In 10 of 23 families where the family history was known, there was defined consanguinity. Five (5) of the remaining 13 families were not known to be consanguineous but originated from genetically isolated populations or populations with known founder effects (e.g., Acadians from the Canadian Maritime Provinces).
All patients presented with reticulocytopenic, microcytic anemia (Table 1). In the 13 individuals in whom pre-transfusion CBC data are available, most of whom were neonates or infants at the time, the mean hemoglobin (HGB) was 5.1 ± 2.4 g/dL (generalized normal range 10.5-13.0 g/dL), mean cell volume (MCV) 61.9 ± 4.9 fL (generalized normal range 79.6-83.3 fL), and absolute reticulocyte count 0.032 ± 0.032 x 106/µL (generalize normal range 0.037-0.104 x106/µL). In 20 of 22 families the diagnosis of CSA was made in the proband by bone marrow aspiration where ring sideroblasts generally constituted >15% of nucleated erythroblasts. In several cases, RS were absent or only rare. In most, but not all, cases, there was an erythroid hyperplasia in the bone marrow; in some there was an erythroid hypoplasia. Conspicuous dyserythropoiesis and variable fibrosis were present in a minority of samples. Anemic siblings were sometimes diagnosed with CSA by genetic testing alone, as was the case with patient 20.2, whose older sibling (20.1), has previously been reported (Kim et al., 2018). Three patients from two families (patients 2.1, 2.2, and 18.1) were initially regarded as having an atypical form of Diamond-Blackfan anemia (DBA). In family 2, the eventual identification of rare siderocytes in the peripheral blood suggested CSA, which was confirmed by candidate gene sequencing. Because of the unusual, apparently syndromic features in patient 14.1, this patient’s diagnosis was established by whole exome sequencing. In patient 18.1, SLC25A38 mutations were identified by whole exome sequencing years after successful hematopoietic stem cell transplantation for “DBA.” Most patients did not have abnormalities in other organ systems that were not attributable to chronic anemia or iron overload (e.g. growth failure, endocrine abnormalities, liver disease, cardiomyopathy), but several potentially syndromic features were observed in a number of patients (Table 1): unilateral corneal clouding (13.1), a “box-shaped” hyperostotic skull (14.1, 24.1), macrocephaly (8.2, 17.1), syndromic facies (28.1), meningomyelocoele/club foot (17.1), genital abnormalities (18.1, 22.3, 22.4), behavioral issues (18.1 and 22.1), aortic root/coronary abnormalities (20.2, 22.2, 22.3).