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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 SMN1 exons 7 and 8. The number of SMN2 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 SMN1 exon 7 deletion and two copies of exon 8 and ≥3 SMN2 copy number in the proband. Results: SMA carrier testing was performed in 118/154 (76.6%) parents, incorporating 59 probands with homozygous SMN1 deletions and one proband with compound heterozygote pathogenic variants. Among parents with a child with SMA, 7.6% had two copies of SMN1 exon 7. When only probands with a homozygous SMN1 exon 7 deletion were included, 6.9% of parents had two copies of SMN1 exon 7. An association was observed between heterozygous deletion of SMN1 exon 7 with two copies of exon 8 in a parent and ≥3 SMN2 copy number in the affected proband (p = 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 SMN2 copy number.

BACKGROUND: A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. METHODS AND RESULTS: Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. SIGNIFICANCE: These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.