# Neurophysiological Profiles in a Family with Multiple SHANK3-Related Phelan–McDermid Syndrome Cases

## TL;DR

This study examines a family with Phelan–McDermid syndrome and finds that a specific brain response is reduced in affected children, suggesting a potential biomarker for the condition.

## Contribution

The study identifies a novel SHANK3 gene variant and demonstrates the 40 Hz ASSR as a potential biomarker for PMS.

## Key findings

- The 40 Hz ASSR was significantly reduced in the younger affected sibling.
- The 40 Hz ASSR was preserved in the unaffected sibling.
- The 40 Hz ASSR may serve as a biomarker for SHANK3-related cortical dysfunction.

## Abstract

We present a family case study of Phelan–McDermid syndrome (PMS), a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene, in which two of three siblings were clinically diagnosed with PMS. Sanger sequencing identified a novel heterozygous deletion in exon 20 of SHANK3 (c.3679del, p.Ala1227Profs*168), predicted to introduce a premature stop codon and truncate the protein; this variant was absent in the unaffected sibling. Auditory steady-state responses (ASSRs) were recorded at 16, 27, and 40 Hz. The 40 Hz ASSR was markedly reduced in both affected siblings, reaching statistical significance in the younger child and remaining non-significant in the older sibling, while it was preserved in the unaffected sibling. These findings suggest that the 40 Hz ASSR is particularly sensitive to SHANK3-related cortical inhibitory dysfunction during childhood and adolescence, with reduced sensitivity in early adulthood. The results highlight the potential of the 40 Hz ASSR as an electrophysiological biomarker in PMS and underscore the need for age-stratified normative control datasets to enable robust individual-level interpretation and support its use in biomarker development, clinical trial stratification, and monitoring of treatment response.