WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

Cara M. Skraban, Constance F. Wells, Preetha Markose, Megan T. Cho, Addie I. Nesbitt, P. Y.Billie Au, Amber Begtrup, John A. Bernat, Lynne M. Bird, Kajia Cao, Arjan P.M. de Brouwer, Elizabeth H. Denenberg, Ganka Douglas, Kristin M. Gibson, Katheryn Grand, Alice Goldenberg, A. Micheil Innes, Jane Juusola, Marlies Kempers, Esther Kinning & 19 others David M. Markie, Martina M. Owens, Katelyn Payne, Richard Person, Rolph Pfundt, Amber Stocco, Claire L.S. Turner, Nienke E. Verbeek, Larry Walsh, Taylor C. Warner, Patricia G. Wheeler, Dagmar Wieczorek, Alisha B. Wilkens, Evelien Zonneveld-Huijssoon, Tjitske Kleefstra, Stephen P. Robertson, Avni Santani, Koen L.I. van Gassen, Matthew A. Deardorff

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

Original languageEnglish (US)
Pages (from-to)139-148
Number of pages10
JournalAmerican Journal of Human Genetics
Volume101
Issue number1
DOIs
StatePublished - Jul 6 2017

Fingerprint

Haploinsufficiency
Gait
Intellectual Disability
Seizures
Mutation
Exome
Muscle Spasticity
Structural Models
Maxilla
Gingiva
Lip
Nose
Tooth
Proteins
Fever
Nucleotides
Chromosomes
RNA
Pathology
Phenotype

Keywords

  • intellectual disability
  • seizure
  • WD-40
  • WDR protein
  • WDR26

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features. / Skraban, Cara M.; Wells, Constance F.; Markose, Preetha; Cho, Megan T.; Nesbitt, Addie I.; Au, P. Y.Billie; Begtrup, Amber; Bernat, John A.; Bird, Lynne M.; Cao, Kajia; de Brouwer, Arjan P.M.; Denenberg, Elizabeth H.; Douglas, Ganka; Gibson, Kristin M.; Grand, Katheryn; Goldenberg, Alice; Innes, A. Micheil; Juusola, Jane; Kempers, Marlies; Kinning, Esther; Markie, David M.; Owens, Martina M.; Payne, Katelyn; Person, Richard; Pfundt, Rolph; Stocco, Amber; Turner, Claire L.S.; Verbeek, Nienke E.; Walsh, Larry; Warner, Taylor C.; Wheeler, Patricia G.; Wieczorek, Dagmar; Wilkens, Alisha B.; Zonneveld-Huijssoon, Evelien; Kleefstra, Tjitske; Robertson, Stephen P.; Santani, Avni; van Gassen, Koen L.I.; Deardorff, Matthew A.

In: American Journal of Human Genetics, Vol. 101, No. 1, 06.07.2017, p. 139-148.

Research output: Contribution to journalArticle

Skraban, CM, Wells, CF, Markose, P, Cho, MT, Nesbitt, AI, Au, PYB, Begtrup, A, Bernat, JA, Bird, LM, Cao, K, de Brouwer, APM, Denenberg, EH, Douglas, G, Gibson, KM, Grand, K, Goldenberg, A, Innes, AM, Juusola, J, Kempers, M, Kinning, E, Markie, DM, Owens, MM, Payne, K, Person, R, Pfundt, R, Stocco, A, Turner, CLS, Verbeek, NE, Walsh, L, Warner, TC, Wheeler, PG, Wieczorek, D, Wilkens, AB, Zonneveld-Huijssoon, E, Kleefstra, T, Robertson, SP, Santani, A, van Gassen, KLI & Deardorff, MA 2017, 'WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features', American Journal of Human Genetics, vol. 101, no. 1, pp. 139-148. https://doi.org/10.1016/j.ajhg.2017.06.002
Skraban, Cara M. ; Wells, Constance F. ; Markose, Preetha ; Cho, Megan T. ; Nesbitt, Addie I. ; Au, P. Y.Billie ; Begtrup, Amber ; Bernat, John A. ; Bird, Lynne M. ; Cao, Kajia ; de Brouwer, Arjan P.M. ; Denenberg, Elizabeth H. ; Douglas, Ganka ; Gibson, Kristin M. ; Grand, Katheryn ; Goldenberg, Alice ; Innes, A. Micheil ; Juusola, Jane ; Kempers, Marlies ; Kinning, Esther ; Markie, David M. ; Owens, Martina M. ; Payne, Katelyn ; Person, Richard ; Pfundt, Rolph ; Stocco, Amber ; Turner, Claire L.S. ; Verbeek, Nienke E. ; Walsh, Larry ; Warner, Taylor C. ; Wheeler, Patricia G. ; Wieczorek, Dagmar ; Wilkens, Alisha B. ; Zonneveld-Huijssoon, Evelien ; Kleefstra, Tjitske ; Robertson, Stephen P. ; Santani, Avni ; van Gassen, Koen L.I. ; Deardorff, Matthew A. / WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features. In: American Journal of Human Genetics. 2017 ; Vol. 101, No. 1. pp. 139-148.
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abstract = "We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.",
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T1 - WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

AU - Skraban, Cara M.

AU - Wells, Constance F.

AU - Markose, Preetha

AU - Cho, Megan T.

AU - Nesbitt, Addie I.

AU - Au, P. Y.Billie

AU - Begtrup, Amber

AU - Bernat, John A.

AU - Bird, Lynne M.

AU - Cao, Kajia

AU - de Brouwer, Arjan P.M.

AU - Denenberg, Elizabeth H.

AU - Douglas, Ganka

AU - Gibson, Kristin M.

AU - Grand, Katheryn

AU - Goldenberg, Alice

AU - Innes, A. Micheil

AU - Juusola, Jane

AU - Kempers, Marlies

AU - Kinning, Esther

AU - Markie, David M.

AU - Owens, Martina M.

AU - Payne, Katelyn

AU - Person, Richard

AU - Pfundt, Rolph

AU - Stocco, Amber

AU - Turner, Claire L.S.

AU - Verbeek, Nienke E.

AU - Walsh, Larry

AU - Warner, Taylor C.

AU - Wheeler, Patricia G.

AU - Wieczorek, Dagmar

AU - Wilkens, Alisha B.

AU - Zonneveld-Huijssoon, Evelien

AU - Kleefstra, Tjitske

AU - Robertson, Stephen P.

AU - Santani, Avni

AU - van Gassen, Koen L.I.

AU - Deardorff, Matthew A.

PY - 2017/7/6

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N2 - We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

AB - We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

KW - intellectual disability

KW - seizure

KW - WD-40

KW - WDR protein

KW - WDR26

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