MISS HOPE TANUDISASTRO1,2,3, DR YUAN MIN WANG1,2, DR DANIEL MACARTHUR3, DR AMALI MALLAWAARACHCHI3,4, DR HUGH MCCARTHY1,2, PROF SI ALEXANDER1,2
1The Children’s Hospital at Westmead, Westmead, Australia, 2The University of Sydney, Camperdown, Australia, 3Garvan Institute of Medical Research, Darlinghurst, Australia, 4Royal Prince Alfred Hospital, Camperdown, Australia
Background
SLC4A1 is a gene that encodes a chloride-bicarbonate exchanger on chromosome 17q21-22. It is highly expressed on erythrocyte membranes and renal alpha-intercalated cells. SLC4A1 variants are implicated in cryohydrocytosis, spherocytosis, and Southeast Asian ovalocytosis (SAO) as well as distal renal tubular acidosis (dRTA). The heterozygous SAO variant (a band 3 deletion of residues 400-408) alters erythrocyte deformability and is protective against malaria caused by Plasmodium falciparum and P. vivax with minimal deleterious effects.
dRTA can be inherited either in an autosomal dominant (AD) or autosomal recessive (AR) pattern. AD dRTA is found commonly in Caucasian populations while AR dRTA is associated with founder variants in Southeast Asia.
Case Report
A patient of Filipino ethnicity presented with distal RTA, hepatosplenomegaly, short stature, and hyperbilirubinaemia. Ultrasound showed bilateral nephrocalcinosis. Bone marrow showed erythroid hyperplasia with marked dyserythropoiesis. Whole genome sequencing (WGS) was performed at Garvan and examined at the Center for Mendelian Genomics at the Broad Institute using the seqr platform. She was found to carry a founder compound heterozygous SCLA4A1 variant (Gly701Asp/Ala400_Ala408del). The missense variant has been reported to act by altering cellular trafficking from the cytoplasm to the basolateral membrane of renal alpha-intercalated cells. The in-frame deletion is associated with SAO and is functionally inactive. Together the two variants, which are enriched in individuals of Southeast Asian ethnicity, lead to insufficient functional protein expression in renal alpha-intercalated cells, contributing to dRTA.
Conclusions
Careful consideration of founder variants in ethnically diverse patients is integral in ensuring equitable genetic interpretation. In this case, the presentation of renal disease and dyserythropoiesis is highly suggestive of a genetic aetiology, which was resolved with WGS.
Biography:
Hope Tanudisastro is a MD student at the University of Sydney and part-time MPhil student at the Children’s Hospital at Westmead and Centre for Population Genomics at the Garvan Institute of Medical Research. She completed a BSc in Genetics and Statistics and has a keen interest in translating advances in genetics and bioinformatics research to clinical practice.