Increased Recurrence Risk in Phelan-McDermid (22q13.3 Deletion) Syndrome: the Importance of FISH Demonstrated by a Case Series of Five Families

Abstract

Background: Phelan-McDermid syndrome (PMS), or 22q13.3 deletion syndrome, is a neurodevelopmental disorder with an estimated prevalence of 1 in 10,000 to 1 in 20,000 newborns. Although it usually occurs de novo with a low recurrence risk, an increased recurrence risk is observed in some families. In this paper, we provide an overview of the underlying causes of increased recurrence risk in families with PMS and present a workflow aimed at identifying an increased recurrence risk. Methods: First, we report clinical and (cyto) genetic data for five families with an increased recurrence risk for PMS from our clinical practices. Second, we provide an overview of cytogenetically investigated Dutch families and literature cases with an increased recurrence risk. Finally, we outline which cytogenetic tests should be performed after diagnosing PMS in a proband. Results: Using fluorescent in situ hybridization (FISH), we found a parental balanced translocation in two of our five families, maternal mosaicism for a ring chromosome 22 in two families, and maternal mosaicism for a pure terminal 22q13.3 deletion in one family. In total, seven of 34 (21%) cytogenetically investigated Dutch families appeared to have an increased recurrence risk. In the medical literature, we found 28 additional families with a parental balanced translocation, and one additional family with parental mosaicism for a ring chromosome 22. Conclusions: An increased recurrence risk in PMS may be more common than currently understood, emphasizing the importance of follow-up FISH testing after PMS diagnosis in a proband. However, as low-grade parental mosaicism may still be missed, prenatal testing should always be offered.