A 3-year-old boy with global developmental delay and profound expressive language impairment presents to the pediatric neurology clinic. Chromosomal microarray reveals a deletion at **A** (22q13.3). His parents report that he is essentially nonverbal despite appearing to understand simple commands. He also has neonatal-onset hypotonia, feeding difficulties, and a concerning history of not crying or withdrawing from painful stimuli. Which of the following best explains the neuropsychiatric phenotype in this child?
A. Loss of SHANK3 function impairs postsynaptic density organization and synaptic plasticity at glutamatergic synapses, critically disrupting excitatory neurotransmission
B. Haploinsufficiency of DiGeorge syndrome genes (22q11.2) causes thymic hypoplasia and immunodeficiency leading to developmental delay
C. Deletion of ELN and LIMK1 on chromosome 7 causes elastin deficiency and connective tissue abnormalities that impair neuronal migration
D. Deletion of SNRPN and UBE3A on chromosome 15 results in loss of paternal gene expression and metabolic dysfunction
Explanation
Why "Loss of SHANK3 function impairs postsynaptic density organization and synaptic plasticity at glutamatergic synapses, critically disrupting excitatory neurotransmission" is right
The deletion at A (22q13.3) in Phelan-McDermid syndrome causes haploinsufficiency of SHANK3, a master scaffolding protein at the postsynaptic density of glutamatergic synapses. SHANK3 organizes NMDA and AMPA receptors and links them to the actin cytoskeleton; loss of SHANK3 critically impairs synaptic plasticity and excitatory neurotransmission. This molecular defect is the principal driver of the neuropsychiatric phenotype, including global developmental delay, severe intellectual disability, profound expressive language impairment (often with preserved receptive language), autism spectrum disorder (~75%), and decreased pain perception. Point mutations in SHANK3 alone reproduce most of this phenotype, confirming SHANK3 as the dominant gene (Nelson Pediatrics 22e, Ch 100).
Why each distractor is wrong
"Haploinsufficiency of DiGeorge syndrome genes (22q11.2) causes thymic hypoplasia and immunodeficiency leading to developmental delay": This describes the deletion at B (22q11.2), not A. DiGeorge syndrome presents with cardiac defects, cleft palate, thymic hypoplasia, and hypocalcemia—not the profound expressive language impairment and pain insensitivity characteristic of Phelan-McDermid.
"Deletion of SNRPN and UBE3A on chromosome 15 results in loss of paternal gene expression and metabolic dysfunction": This describes the deletion at C (15q11.2), which causes Prader-Willi syndrome. Prader-Willi presents with neonatal hypotonia, feeding difficulty, and obesity—not the striking expressive language impairment or autism prevalence seen in Phelan-McDermid.
"Deletion of ELN and LIMK1 on chromosome 7 causes elastin deficiency and connective tissue abnormalities that impair neuronal migration": This describes the deletion at D (7q11.23), which causes Williams syndrome. Williams presents with supravalvular aortic stenosis, elfin facies, and hypercalcemia—not the profound nonverbal presentation or pain insensitivity of Phelan-McDermid.
High-YieldNEET PG
SHANK3 loss in Phelan-McDermid is the principal driver of neuropsychiatric phenotype; profound expressive language impairment with relatively preserved receptive language is a striking clinical hallmark that distinguishes it from other 22q deletions.
Nelson Pediatrics 22e, Ch 100
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