Disease and Health Research: Recent Developments Vol. 1

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder in which carrier screening may be difficult when copy number findings do not correspond with family history. This chapter describes a 28-year-old woman who sought genetic counselling and prenatal diagnosis after two previous children had been affected with SMA type 1 and had died at 6 months of age. The couple was non-consanguineous. Genetic evaluation of an affected child showed no point mutation on exome sequencing, whereas multiplex ligation-dependent probe amplification identified homozygous deletion of exons 7 and 8 of the SMN1 gene. Segregation analysis showed that the mother carried a single copy of SMN1, consistent with carrier status, while the father had two SMN1 copies on dosage testing and appeared to be a non-carrier. In view of the family history, a paternal silent carrier state caused by a cis SMN1 copy configuration was suspected. During the current pregnancy, chorionic villus sampling was performed at 12 weeks. Initial foetal testing raised concern for sex chromosome aneuploidy, and amniocentesis at 16 weeks was performed for clarification. Amniotic fluid evaluation showed a 46,XY karyotype and two copies of SMN1. The pregnancy was continued, and a healthy child was delivered at term. This case highlights the need to interpret SMA carrier screening in relation to clinical history, previous affected offspring and the limitations of dosage-based assays.