40-Hz Auditory Steady-State Response (ASSR) as a Biomarker of Genetic Defects in the SHANK3 Gene: A Case Report of 15-Year-Old Girl with a Rare Partial SHANK3 Duplication

Abstract

SHANK3 encodes a scaffold protein involved in postsynaptic receptor density in glutamatergic synapses, including those in the parvalbumin (PV)+ inhibitory neurons—the key players in the generation of sensory gamma oscillations, such as 40-Hz auditory steady-state response (ASSR). However, 40-Hz ASSR was not studied in relation to SHANK3 functioning. Here, we present a 15-year-old girl (SH01) with previously unreported duplication of the first seven exons of the SHANK3 gene (22q13.33). SH01’s electroencephalogram (EEG) during 40-Hz click trains of 500 ms duration binaurally presented with inter-trial intervals of 500–800 ms were compared with those from typically developing children (n = 32). SH01 was diagnosed with mild mental retardation and learning disabilities (F70.88), dysgraphia, dyslexia, and smaller vocabulary than typically developing (TD) peers. Her clinical phenotype resembled the phenotype of previously described patients with 22q13.33 microduplications (≈30 reported so far). SH01 had mild autistic symptoms but below the threshold for ASD diagnosis and microcephaly. No seizures or MRI abnormalities were reported. While SH01 had relatively preserved auditory event-related potential (ERP) with slightly attenuated P1, her 40-Hz ASSR was totally absent significantly deviating from TD’s ASSR. The absence of 40-Hz ASSR in patients with microduplication, which affected the SHANK3 gene, indicates deficient temporal resolution of the auditory system, which might underlie language problems and represent a neurophysiological biomarker of SHANK3 abnormalities.

22q13.33 duplication involving SHANK3 gene: a boy and his mother with “persistent” language and speech sound disorder

“…Such data indicate persistent difficulty carrying out phonological analysis of words. Temporal resolution deficiency of auditory system has recently been hypothesized in a 15-year-old girl with a partial SHANK3 duplication (Neklyudova et al ., 2021) and could underlie spelling and language problems comparable to that of our patient.…”

“…Array-CGH is often performed in case of ASD and ID (Battaglia et al , 2013; Cappuccio et al , 2016), but rarely for other neurodevelopmental disorders, but in our family the presence of “persistent” Language and Speech Disorder in the boy and in his mother and very mild peculiar facial features prompted to perform genetic tests which highlighted 22q13.33 microduplication disrupting SHANK3 gene in both. Speech and language problems are characteristic of SHANK3 overexpression but always described in comorbidity with ID or ASD (Johannessen et al , 2019; Ujfalusi et al , 2020; Neklyudova et al , 2021). Our patient and his mother are the only patients who show persistent speech and language problems in absence of ID or ASD.…”

“…Among the 31 patients described in literature with 22q13.33 duplication (Failla et al, 2007;Okamoto et al, 2007;Pinto et al, 2010;Destrée et al, 2011;Han et al, 2013;Chen et al, 2017;Johannessen et al, 2019;Ujfalusi et al, 2020;Neklyudova et al, 2021;decipher.sanger.ac.uk database (a)), only 4 cases present a cytogenetic alteration disrupting SHANK3 gene. Three of them are described in decipher.sanger.ac.uk database, and the fourth patient was recently described by Neklyudova (Neklyudova et al, 2021;decipher.sanger.ac.uk database (b)). Variable phenotype is described in these patients including ID, ASD, small vocabulary, anxiety, learning disorders, behavioral problems and only in one case isolated somatic malformations (coarctation of aorta, renal dysplasia, ventricular septal defect).…”

Atypical brain responses to 40‐Hz click trains in girls with Rett syndrome: Auditory steady‐state response and sustained wave

“…when PV+ interneurons are affected, as in RTT. We previously reported that ASSR is diminished in children with mutations in the SHANK3 gene, 38,39 which also leads to improper functioning of PV+ interneurons.…”

Responses at Individual Gamma Frequencies Are Related to the Processing Speed but Not the Inhibitory Control

“…The gamma-range auditory steady-state response (ASSR) is frequently employed in neuropsychiatric disorders to assess deficits in gamma generation potential, and results are often discussed in relation to changed cognitive functioning [ 3 , 5 , 6 ]. As gamma-range ASSRs reflect the imbalance between inhibition and excitation in the brain circuits [ 3 , 7 , 8 ], the alterations of ASSRs are observed already in ultra-high-risk subjects [ 9 ] and show the promise to track the response to treatment [ 10 , 11 ], thus being a potentially sensitive marker of conditions where subtle changes in the state could occur. However, the link between the state of networks underlying the generation of periodic responses at gamma ranges and cognitive outcomes is still poorly understood.…”