A SHANK3 Point Mutation with Phelan-Mcdermid Phenotype, Notably without Autism Spectrum Disorder or Intellectual Deficits

Background:   The SHANK3 gene encodes a scaffolding protein in the cortex and cerebellum that plays a role in synaptic signal transmission. SHANK3 is disrupted in Phelan-McDermid Syndrome (PMS or 22q13.3 deletion syndrome), which is characterized by variable central nervous dysfunction including speech and motor delays, hypotonia, Intellectual Deficits (ID), and Autism Spectrum Disorder (ASD). Expressive language is typically more impaired than receptive language.  There is evidence larger deletions correlate with greater developmental dysfunction and higher rates of ASD.  As many as 84% of individuals with PMS are also diagnosed with ASD.  SHANK3 haploinsufficiency is also implicated in ASD, and is present in 0.5% of ASD cases (one of the largest monogenic causes of ASD) and 2% of moderate-to-profound ID cases. 

Objectives: N/A

Methods: N/A

Results:  We present a 5 year-old girl with a single point c.2265+3 A>T variant in intron 19 in the SHANK3 gene.

She has a history of developmental regression, limb asymmetry, advanced bone age, and coordination difficulties.  Feeding disturbances and speech delay with intermittent regression of skills were noted at 18 months. She is diagnosed with Childhood Apraxia of Speech (CAS) with  facial and truncal hypotonia, motor difficulties, balance problems, oculomotor apraxia, and visual perceptual deficits (SS=74 on VMI).  GARS-2 and GADS scores are below the first percentile, however,the SRS-2 revealed mildly atypical scores in social cognition and social awareness with T-scores of 63 and 62, respectively, compared to a Total T-Score of 56.  Intellectual function tends to be in the average range (90-109), with a Fluid Reasoning (FR) of 93, Working Memory Index (WMI) of 103, and a Verbal Comprehension Index (VCI) of 81 (low average).  Expressive and receptive vocabulary scores were 97 and 103 on EOWPVT-R and ROWPVT-R, respectively.

Her phenotypic profile including facial dysmorphisms and neurodevelopmental profile are characteristic of  PMS, while she does not meet criteria for ASD. 

Conclusions:  This report highlights the first case –to our knowledge– where a single-point mutation in the SHANK3 gene has resulted in a constellation of findings associated with PMS, supporting that SHANK3 is critical to the PMS phenotype, and that smaller deletions/ mutations correlate with more normalized  neurocognitive function.  Critically, this case supports higher intellectual capability than has been previously reported in patients with SHANK3 mutations (typically ranging from moderate to severe ID).

Also significant, while the majority of patients with SHANK3 mutations and deletions have ASD, this patient shows no significant ASD features but does have some social language issues.  This fits with the literature showing that smaller deletions/mutations correlate with lower rates of ASD diagnosis, as well as the fact that ASD is not inherent in cases of SHANK3 mutation.  

Lastly, this case is novel in that the patient is diagnosed with CAS.  While language delay (especially expressive) is consistently reported in PMS, diagnosed CAS is unreported.  Further investigation is merited to evaluate whether CAS is more prevalent in PMS than is currently documented, as well as its potential contribution to the phenotype, especially the delayed speech, expressive language disorder, and any oral motor deficits.