Summary
In a case study, a 6-year-old boy exhibiting a phenotype characterized by intrauterine growth restriction, low birth weight, neonatal hypotonia, psychomotor delay, marphanoid habitus, muscle hypotrophy, facial dysmorphisms, cryptorchidism, shawl scrotum, mild clinodactyly of the right little finger, bilateral syndactyly of the II and III toes with sandal gap, delayed bone age, and mild mitral prolapse was identified as having a heterozygous de novo deletion in the NSD2 gene (c.2523delG), predicted to cause a loss of function. The deletion was verified as de novo, indicating that it was not inherited from the patient's parents. The clinical features associated with NSD2 gene haploinsufficiency are commonly growth restriction, facial gestalt, intellectual disability, microcephaly, clinodactyly, and developmental delay, with autism spectrum disorder reported in a subset of NSD2-haploinsufficient children. Functional studies, including exome sequencing analyses and observational investigations, support the correlation between loss-of-function variants like disruptions in NSD2 and clinical outcomes such as developmental delay and autism spectrum disorder. Such evidence underpins the consideration of NSD2 haploinsufficiency as contributing to the clinical spectrum consistent with atypical or partial Wolf-Hirschhorn Syndrome (WHS).
Evidence of Haploinsufficiency
Patient Identifier: 6-year-old boy
Mutation Type: deletion
Mutation Details: heterozygous de novo variant of NSD2 (c.2523delG)
Clinical Phenotype: intrauterine growth restriction, low birth weight, neonatal hypotonia, psychomotor delay, marphanoid habitus, muscle hypotrophy, facial dysmorphisms, cryptorchidism, shawl scrotum, mild clinodactyly of the right little finger, bilateral syndactyly of the II and III toes with sandal gap, delayed bone age, mild mitral prolapse
Inheritance Tested: Yes
Effect on Gene Function: predicted loss of function
Direct Quote: "Whole genome sequencing analysis revealed a heterozygous de novo variant of NSD2 (c.2523delG)."
Location in Paper: Case presentation
Clinical Features
Feature: growth restriction
Frequency: common
Direct Quote: "whose core phenotype encompasses growth restriction"
Location in Paper: AbstractBackground
Feature: facial gestalt
Frequency: common
Direct Quote: "whose core phenotype encompasses ... facial gestalt"
Location in Paper: AbstractBackground
Feature: intellectual disability
Frequency: common
Direct Quote: "whose core phenotype encompasses ... intellectual disability"
Location in Paper: AbstractBackground
Feature: microcephaly
Frequency: common
Direct Quote: "presenting some of the typical findings of WHS (intellectual disability, facial gestalt, microcephaly, growth restriction and congenital heart defects)"
Location in Paper: AbstractBackground
Feature: clinodactyly
Frequency: common
Direct Quote: "NSD2-deleted children tend to display a milder spectrum of skeletal abnormalities, usually consisting of clinodactyly"
Location in Paper: AbstractBackground
Feature: developmental delay
Frequency: common
Direct Quote: "this hypothesis has been further supported by the documentation of a higher degree of developmental delay in patients with disrupted NSD2, compared with those with the intact gene."
Location in Paper: Discussion and conclusions
Feature: Autism spectrum disorder
Frequency: reported in eight NSD2-haploinsufficient children
Direct Quote: "Autism spectrum disorder has been reported in eight NSD2-haploinsufficient children."
Location in Paper: Discussion and conclusions
Functional Studies
Study Type: exome sequencing analyses
Methodology: identification of loss-of-function variants in the WHSCR
Conclusions: loss-of-function variants contribute to a clinical spectrum consistent with atypical or partial WHS
Direct Quote: "More recently, exome sequencing analyses identified two genes within the WHSCR, whose loss-of-function variants contribute to a clinical spectrum consistent with atypical or partial WHS: WHSC1, also known as Nuclear receptor-binding Set Domain-protein 2 (NSD2)."
Location in Paper: Background
Study Type: Observational study
Methodology: Comparison of developmental delay in patients with disrupted NSD2 vs. those with intact NSD2
Conclusions: Documentation of a higher degree of developmental delay in patients with disrupted NSD2
Direct Quote: "This hypothesis has been further supported by the documentation of a higher degree of developmental delay in patients with disrupted NSD2, compared with those with the intact gene [8, 9]"
Location in Paper: Paragraph 1
Study Type: Clinical correlation study
Methodology: Correlation of NSD2 haploinsufficiency with autism spectrum disorder
Conclusions: Autism spectrum disorder reported in eight NSD2-haploinsufficient children
Direct Quote: "Autism spectrum disorder has been reported in eight NSD2-haploinsufficient children [10, 11]"
Location in Paper: Paragraph 1
Study Type: Clinical observation
Methodology: Observation of facial features in patients with microdeletions with and without NSD2 involvement
Conclusions: Deletions of NSD2 are considered responsible for the facial gestalt of WHS
Direct Quote: "Deletions of NSD2 are considered responsible for the facial gestalt of WHS, in light of the observation of non-specific findings consistent with WHS (growth and developmental delay) but without the typical dysmorphic features, in several patients with microdeletions sparing NSD2"
Location in Paper: Paragraph 1