NRXN1 – Pitt-Hopkins-like syndrome 2

Heterozygous deletions of the NRXN1 gene at 2p16.3 have been reported in two related individuals presenting with a Pitt-Hopkins-like syndrome 2 phenotype, including neurodevelopmental delay, macrocephaly, turricephaly, strabismus, and large for gestational age (PMID:35626875). Both twins carried the same microdeletion detected by array comparative genomic hybridization, while their father also harbored the deletion but remained asymptomatic, indicating incomplete penetrance and variable expressivity. No other families or unrelated probands have been documented for this specific phenotype, and segregation analysis beyond this single pedigree is lacking. Functional studies directly linking NRXN1 haploinsufficiency to the Pitt-Hopkins-like syndrome 2 clinical spectrum have not yet been reported, although neurexin-1’s role in synaptic organization suggests a plausible pathogenic mechanism.

Clinical Validity: Limited – evidence derives from two probands in a single family with heterozygous NRXN1 deletion and no confirmed segregation beyond reduced penetrance (PMID:35626875).

Genetic Evidence: Limited – only two affected siblings reported; no additional segregation or unrelated cases.

Functional Evidence: Limited – absence of targeted mechanistic studies in relevant neuronal models for this phenotype.

Key Take-home: While NRXN1 deletions can underlie a Pitt-Hopkins-like neurodevelopmental syndrome, current evidence is restricted to a single family, underscoring the need for broader case series and functional characterization to inform diagnosis and genetic counseling.

References

• Children (Basel, Switzerland) • 2022 • NRXN1 Deletion in Two Twins' Genotype and Phenotype: A Clinical Case and Literature Review. PMID:35626875

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