Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability

Wenmiao Zhu, Jianli Li, Stella Chen, Jinglan Zhang, Francesco Vetrini, Alicia Braxton, Christine M. Eng, Yaping Yang, Fan Xia, Kory Keller, Leila Okinaka-Hu, Chung Lee, J. Lloyd Holder, Weimin Bi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.

Original languageEnglish (US)
JournalAmerican Journal of Medical Genetics, Part A
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Autistic Disorder
Intellectual Disability
Exons
Language
Alleles
Exome
Post-Synaptic Density
Failure to Thrive
Polymerase Chain Reaction
Microcephaly
Mutation
CpG Islands
Neurotransmitter Receptor
Inguinal Hernia
Sequence Deletion
Ataxia
Constipation
Cytoskeleton
Synapses
Lower Extremity

Keywords

  • De novo
  • Double mutations on one allele
  • Phelan-McDermid syndrome
  • SHANK3
  • Variant phasing
  • Whole exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability. / Zhu, Wenmiao; Li, Jianli; Chen, Stella; Zhang, Jinglan; Vetrini, Francesco; Braxton, Alicia; Eng, Christine M.; Yang, Yaping; Xia, Fan; Keller, Kory; Okinaka-Hu, Leila; Lee, Chung; Holder, J. Lloyd; Bi, Weimin.

In: American Journal of Medical Genetics, Part A, 01.01.2018.

Research output: Contribution to journalArticle

Zhu, W, Li, J, Chen, S, Zhang, J, Vetrini, F, Braxton, A, Eng, CM, Yang, Y, Xia, F, Keller, K, Okinaka-Hu, L, Lee, C, Holder, JL & Bi, W 2018, 'Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability', American Journal of Medical Genetics, Part A. https://doi.org/10.1002/ajmg.a.38622
Zhu, Wenmiao ; Li, Jianli ; Chen, Stella ; Zhang, Jinglan ; Vetrini, Francesco ; Braxton, Alicia ; Eng, Christine M. ; Yang, Yaping ; Xia, Fan ; Keller, Kory ; Okinaka-Hu, Leila ; Lee, Chung ; Holder, J. Lloyd ; Bi, Weimin. / Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability. In: American Journal of Medical Genetics, Part A. 2018.
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AU - Yang, Yaping

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AB - SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.

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