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Null variants and deletions in BRWD3 cause an X-linked syndrome of mold-moderate intellectual disability, macrocephaly, and obesity: a series of 17 patients

Null variants and deletions in BRWD3 cause an X-linked syndrome of mold-moderate intellectual disability, macrocephaly, and obesity: a series of 17 patients
Null variants and deletions in BRWD3 cause an X-linked syndrome of mold-moderate intellectual disability, macrocephaly, and obesity: a series of 17 patients
BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and two partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.
1552-4868
638-643
Ostrowski, Philip
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Zachariou, Anna
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Loveday, Chey
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Baralle, Diana
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Blair, Ed
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Douzgou, Sofia
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Field, Michael
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Foster, Alison C.
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Kyle, Claire
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Lachlan, Katherine
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Mansour, Sahar
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Naik, Swati
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Rea, Gillian
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Smithson, Sarah
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Sznajer, Yves
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Thompson, Elizabeth
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Cole, Trevor
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Tatton-Brown, Katrina
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Ostrowski, Philip
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Zachariou, Anna
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Loveday, Chey
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Baralle, Diana
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Blair, Ed
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Douzgou, Sofia
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Field, Michael
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Foster, Alison C.
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Kyle, Claire
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Lachlan, Katherine
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Mansour, Sahar
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Naik, Swati
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Rea, Gillian
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Smithson, Sarah
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Sznajer, Yves
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Thompson, Elizabeth
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Cole, Trevor
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Tatton-Brown, Katrina
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Ostrowski, Philip, Zachariou, Anna, Loveday, Chey, Baralle, Diana, Blair, Ed, Douzgou, Sofia, Field, Michael, Foster, Alison C., Kyle, Claire, Lachlan, Katherine, Mansour, Sahar, Naik, Swati, Rea, Gillian, Smithson, Sarah, Sznajer, Yves, Thompson, Elizabeth, Cole, Trevor and Tatton-Brown, Katrina (2019) Null variants and deletions in BRWD3 cause an X-linked syndrome of mold-moderate intellectual disability, macrocephaly, and obesity: a series of 17 patients. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 181 (4), 638-643. (doi:10.1002/ajmg.c.31750).

Record type: Article

Abstract

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and two partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.

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BRWD3 revised proof - Accepted Manuscript
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Accepted/In Press date: 11 October 2019
e-pub ahead of print date: 12 November 2019
Published date: 1 December 2019
Additional Information: Special Issue: Overgrowth Syndrome

Identifiers

Local EPrints ID: 435055
URI: http://eprints.soton.ac.uk/id/eprint/435055
ISSN: 1552-4868
PURE UUID: a660cf56-7cef-414b-a3b6-adf8a440a8e6
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 21 Oct 2019 16:30
Last modified: 22 Nov 2021 07:45

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Contributors

Author: Philip Ostrowski
Author: Anna Zachariou
Author: Chey Loveday
Author: Diana Baralle ORCID iD
Author: Ed Blair
Author: Sofia Douzgou
Author: Michael Field
Author: Alison C. Foster
Author: Claire Kyle
Author: Katherine Lachlan
Author: Sahar Mansour
Author: Swati Naik
Author: Gillian Rea
Author: Sarah Smithson
Author: Yves Sznajer
Author: Elizabeth Thompson
Author: Trevor Cole
Author: Katrina Tatton-Brown

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