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).