NEXT GENERATION SEQUENCING OF AN AUSTRALIAN FAMILY TO IDENTIFY THE GENETIC BASIS OF A RARE BLOOD GROUP ANTIGEN — The Association Specialists
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NEXT GENERATION SEQUENCING OF AN AUSTRALIAN FAMILY TO IDENTIFY THE GENETIC BASIS OF A RARE BLOOD GROUP ANTIGEN (262)

Rhiannon McBean 1 , Tony Roscioli 2 , Catherine Hyland 1 , Robert Flower 1
  1. Australian Red Cross Blood Service, Kelvin Grove, QLD, Australia
  2. SEALS Molecular and Cytogenetics Laboratory, Prince of Wales Hospital, Sydney, NSW, Australia

Background:  The low-frequency SARAH red blood cell (RBC) antigen was discovered in Australia in 1990. Recently, SARAH incompatibility was implicated in a case of severe Hemolytic Disease of the Fetus and Newborn (HDFN). In light of this, the SARAH proband was exome sequenced to identify the genetic basis of SARAH. Sequencing identified 20 024 exonic single nucleotide variants (SNV) with further SNV filtering not possible. The cooperation of the family was obtained to undertake a full genetic study.

Aim:  To identify the genetic basis of the SARAH antigen.

Methods:  Nine family members (six SARAH positive) from three generations were recruited to this study. DNA samples were exome sequenced by the Australian Genome Research Facility using the Agilent SureSelect All Exon v4 +UTR kit on an Illumina HiSeq2000. Sequence alignment was performed with Illumina CASAVA v1.8.2, mapping to the reference genome HG19.

Results:  Sequencing identified 499 329 SNVs, with 73 782 SNVs common between all family members. SNV filtering was performed to exclude SNVs with a NCBI dbSNP ID (n= 482 177) and non-protein coding SNVs (n= 14 008). SNVs not present in all six positive family members only, were also excluded. Following filtering, one SNV in the Glycophorin A (GYPA) gene was identified. This SNV is not in the 1000 Genomes Project (1000G) or Exome Sequencing Project (ESP6500) databases, further confirming this SNV is novel and of low-frequency.

Conclusions:  A putative genetic basis for SARAH was identified in a GYPA region known to contain several SNVs leading to antigenic change. Missense variants from this region of GYPA, notably the Martin (Mta) polymorphism, have also been associated with HDFN. Confirmation of the genetic basis of SARAH will allow this polymorphism to be included in genotyping screens for GYPA SNVs to determine the basis of incompatibility in future cases of HDFN.