The Carrier Frequency of Two Genes in Parents of Symptomatic Children with SMA and the Significance of Exon 8 in Carriers.

Background: Current carrier screening methods do not identify a proportion of carriers that may have children affected by spinal muscular atrophy (SMA). Additional genetic data is essential to inform accurate risk assessment and genetic counselling of SMA carriers. This study aims to quantify the various genotypes among parents of children with SMA.

Method: A retrospective cohort study was undertaken at Sydney Children's Hospital Network, the major SMA referral centre for New South Wales, Australia. Participants included children with genetically confirmed SMA born between 2005 and 2021. Data was collected on parent genotype inclusive of copy number of exons 7 and 8. The number of exon 7 copies were recorded for the affected children. Descriptive statistics were used to determine the proportion of carriers of 2+0 genotype classified as silent carriers. Chi-square test was used to correlate the association between parents with a heterozygous exon 7 deletion and two copies of exon 8 and ≥3 copy number in the proband.

Results: SMA carrier testing was performed in 118/154 (76.6%) parents, incorporating 59 probands with homozygous deletions and one proband with compound heterozygote pathogenic variants. Among parents with a child with SMA, 7.6% had two copies of exon 7. When only probands with a homozygous exon 7 deletion were included, 6.9% of parents had two copies of exon 7. An association was observed between heterozygous deletion of exon 7 with two copies of exon 8 in a parent and ≥3 copy number in the affected proband ( = 0.07).

Conclusions: This study confirmed a small but substantial proportion of silent carriers not identified by conventional screening within an Australian context. Accordingly, the effectiveness of carrier screening for SMA is linked with genetic counselling to enable health literacy regarding high and low risk results and is complemented by new-born screening and maintaining clinical awareness for SMA. Gene conversion events may underpin the associations between parent carrier status and proband copy number.