De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability

DDD Study

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1 Citation (Scopus)

Abstract

DDX3X (Xp11.4) encodes a DEAD-box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X-linked intellectual disability (ID) (MRX102, MIM: 300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss-of-function variants in this gene are suspected to be male lethal. Through whole-exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.

Original languageEnglish (US)
JournalAmerican Journal of Medical Genetics, Part A
DOIs
StatePublished - Jan 1 2019

Fingerprint

Intellectual Disability
Phenotype
DEAD-box RNA Helicases
Exome
Haploinsufficiency
X Chromosome Inactivation
Microcephaly
Muscle Hypotonia
Movement Disorders
Computer Simulation
Virulence
Alleles
Mothers
Mutation
Brain
Genes

Keywords

  • DDX3X
  • developmental delay
  • intellectual disability
  • syndromic intellectual disability

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

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title = "De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability",
abstract = "DDX3X (Xp11.4) encodes a DEAD-box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X-linked intellectual disability (ID) (MRX102, MIM: 300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss-of-function variants in this gene are suspected to be male lethal. Through whole-exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.",
keywords = "DDX3X, developmental delay, intellectual disability, syndromic intellectual disability",
author = "{DDD Study} and Pantelis Nicola and Blackburn, {Patrick R.} and Rasmussen, {Kristen J.} and Bertsch, {Nicole L.} and Klee, {Eric W} and Linda Hasadsri and Pichurin, {Pavel N.} and Julia Rankin and Raymond, {F. Lucy} and Jill Clayton-Smith",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/ajmg.a.61061",
language = "English (US)",
journal = "American Journal of Medical Genetics, Part A",
issn = "0148-7299",
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TY - JOUR

T1 - De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability

AU - DDD Study

AU - Nicola, Pantelis

AU - Blackburn, Patrick R.

AU - Rasmussen, Kristen J.

AU - Bertsch, Nicole L.

AU - Klee, Eric W

AU - Hasadsri, Linda

AU - Pichurin, Pavel N.

AU - Rankin, Julia

AU - Raymond, F. Lucy

AU - Clayton-Smith, Jill

PY - 2019/1/1

Y1 - 2019/1/1

N2 - DDX3X (Xp11.4) encodes a DEAD-box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X-linked intellectual disability (ID) (MRX102, MIM: 300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss-of-function variants in this gene are suspected to be male lethal. Through whole-exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.

AB - DDX3X (Xp11.4) encodes a DEAD-box RNA helicase that escapes X chromosome inactivation. Pathogenic variants in DDX3X have been shown to cause X-linked intellectual disability (ID) (MRX102, MIM: 300958). The phenotypes associated with DDX3X variants are heterogeneous and include brain and behavioral abnormalities, microcephaly, hypotonia, and movement disorders and/or spasticity. The majority of DDX3X variants described are de novo mutations in females with ID. In contrast, most male DDX3X variants are inherited from an unaffected mother, with one documented exception being a recently identified de novo splice site variant. It has been suggested, therefore, that DDX3X exerts its effects through haploinsufficiency in females, and that affected males carry hypomorphic alleles that retain partial function. Given the lack of male de novo DDX3X variants, loss-of-function variants in this gene are suspected to be male lethal. Through whole-exome sequencing, we identified three unrelated males with hemizygous missense DDX3X variants and ID. All three variants were confirmed by Sanger sequencing, with two established as de novo. In silico analyses were supportive of pathogenicity. We report the male phenotypes and compare them to phenotypes observed in previously reported male and female patients. In conclusion, we propose that de novo DDX3X variants are not necessarily male lethal and should be considered as a cause of syndromic ID in both males and females.

KW - DDX3X

KW - developmental delay

KW - intellectual disability

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JO - American Journal of Medical Genetics, Part A

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