Family Leaders Navigate Burden to Communicate Risk during Cascade Screening after Sudden Cardiac Death in the Young.

Neurexin 1 (NRXN1) is a pre-synaptic adhesion molecule that plays important roles in synapse formation, maintenance, regulation and function (). The locus is particularly susceptible to non-recurrent copy-number variants (i.e. unique genomic changes that occur at different locations in different individuals), and deletions have been associated with multiple neurodevelopmental disorders including autism, schizophrenia, intellectual disability and developmental delay (). While most individuals ascertained to date have monoallelic deletions, biallelic deletions have been observed in a small group of individuals diagnosed with Pitt−Hopkins syndrome, who display significant developmental delay (; ). Genomic studies have described three different promoters at human and mouse loci that generate three evolutionarily conserved NRXN1 isoforms known as α, β and γ (). While their intracellular domains are identical, their extracellular domains differ, with the α isoform being the longest, the β isoform being intermediate in length and the γ isoform being the shortest. To date, α-isoform-specific exonic deletions located in the 5′ region of have been strongly associated with clinically defined behavioral phenotypes (), suggesting that, compared to deletions affecting β or γ isoforms, exonic disruption of the region yielding the NRXN1 α isoform (NRXN1-α) may have a major impact on behavior and, thus, be more pathogenic. However, deletions involving the β isoform have also been identified in individuals with clinical phenotypes (; ), suggesting a more nuanced view. Indeed, recent work has suggested that 5′ and 3′ deletions can act through divergent molecular mechanisms (; ) requiring altogether different interventions. Therefore, understanding if and to which degree NRXN1 isoform-specific deletions impact behavioral outcomes is essential to define the spectrum of disease mechanisms. In turn, this knowledge may ultimately predict more fine-tuned and divergent therapeutic interventions. To date, most behavioral studies of NRXN1 isoforms have focused on mammalian α. These studies reveal that in mice, homozygous Nrxn1 deletions specific for NRXN1α cause multiple behavioral abnormalities, including alterations in social behavior, locomotion and anxiety (; ; ) that are inconsistently seen across studies in heterozygous animals (; ; ; ). Surprisingly, analogous studies evaluating the function of the NRXN1-β or -γ isoforms and whole-gene deletions spanning all isoforms have so far not been conducted.