TY - JOUR
T1 - Two de novo novel mutations in one SHANK3 allele in a patient with autism and moderate intellectual disability
AU - Zhu, Wenmiao
AU - Li, Jianli
AU - Chen, Stella
AU - Zhang, Jinglan
AU - Vetrini, Francesco
AU - Braxton, Alicia
AU - Eng, Christine M.
AU - Yang, Yaping
AU - Xia, Fan
AU - Keller, Kory L.
AU - Okinaka-Hu, Leila
AU - Lee, Chung
AU - Holder, J. Lloyd
AU - Bi, Weimin
N1 - Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
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.
KW - Phelan-McDermid syndrome
KW - SHANK3
KW - de novo
KW - double mutations on one allele
KW - variant phasing
KW - whole exome sequencing
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U2 - 10.1002/ajmg.a.38622
DO - 10.1002/ajmg.a.38622
M3 - Article
C2 - 29423971
AN - SCOPUS:85041723777
SN - 1552-4825
VL - 176
SP - 973
EP - 979
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 4
ER -