NRXN1
undergoes extensive alternative splicing, and non-recurrent heterozygous deletions in
NRXN1
are strongly associated with neuropsychiatric disorders. We establish that human induced pluripotent stem cell (hiPSC)-derived neurons represent well the diversity of
NRXN1α
alternative splicing observed in the human brain, cataloguing 123 high-confidence in-frame human
NRXN1α
isoforms. Patient-derived
NRXN1
+/−
hiPSC-neurons show greater than two-fold reduction of half of the wild-type
NRXN1α
isoforms and express dozens of novel isoforms expressed from the mutant allele. Reduced neuronal activity in patient-derived
NRXN1
+/−
hiPSC-neurons is ameliorated by overexpression of individual control isoforms in a genotype-dependent manner, whereas individual mutant isoforms decrease neuronal activity levels in control hiPSC-neurons. In a genotype-dependent manner, the phenotypic impact of patient-specific
NRXN1
+/−
mutations can occur through a reduction in wild-type
NRXN1α
isoform levels as well as the presence of mutant
NRXN1α
isoforms.
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