Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders
Anushree Acharya
(1)
,
Haluk Kavus
(2)
,
Patrick Dunn
(3)
,
Abdul Nasir
(4)
,
Leandra Folk
(5)
,
Kara Withrow
(5)
,
Ingrid M Wentzensen
(5)
,
Maura R Z Ruzhnikov
(6)
,
Camille Fallot
(7)
,
Thomas Smol
(8, 7, 9)
,
Mélanie Rama
(7, 9)
,
Kathleen Brown
(10)
,
Sandra Whalen
(11, 12)
,
Alban Ziegler
(13)
,
Magali Barth
(13)
,
Anna Chassevent
(14)
,
Constance Smith-Hicks
(15)
,
Alexandra Afenjar
(11, 12)
,
Thomas Courtin
(16)
,
Solveig Heide
(16, 12)
,
Esperanza Font-Montgomery
(17)
,
Caleb Heid
(17)
,
J. Austin Hamm
,
Donald R Love
(18)
,
Farouq Thabet
(18)
,
Vinod K Misra
(19, 20)
,
Mitch Cunningham
(19)
,
Suzanne M Leal
(1)
,
Irma Jarvela
(21)
,
Elizabeth A Normand
(5)
,
Fanggeng Zou
(5)
,
Mayada Helal
(2)
,
Boris Keren
(16)
,
Erin Torti
(5)
,
Wendy K Chung
(2)
,
Isabelle Schrauwen
(1)
1
CUMC -
Columbia University Medical Center
2 Columbia University [New York]
3 GW - The George Washington University
4 University of Agriculture Faisalabad - UAF (PAKISTAN)
5 GeneDx [Gaithersburg, MD, USA]
6 Stanford University
7 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
8 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
9 Institut de génétique médicale
10 University of Colorado Anschutz [Aurora]
11 CHU Trousseau [APHP]
12 SU - Sorbonne Université
13 CHU Angers - Centre Hospitalier Universitaire d'Angers
14 Kennedy Krieger Institute [Baltimore]
15 Johns Hopkins University School of Medicine [Baltimore]
16 CHU Pitié-Salpêtrière [AP-HP]
17 Mizzou - University of Missouri [Columbia]
18 Sidra Medicine [Doha, Qatar]
19 Children's Hospital of Michigan
20 CMU - Central Michigan University
21 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
2 Columbia University [New York]
3 GW - The George Washington University
4 University of Agriculture Faisalabad - UAF (PAKISTAN)
5 GeneDx [Gaithersburg, MD, USA]
6 Stanford University
7 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
8 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
9 Institut de génétique médicale
10 University of Colorado Anschutz [Aurora]
11 CHU Trousseau [APHP]
12 SU - Sorbonne Université
13 CHU Angers - Centre Hospitalier Universitaire d'Angers
14 Kennedy Krieger Institute [Baltimore]
15 Johns Hopkins University School of Medicine [Baltimore]
16 CHU Pitié-Salpêtrière [AP-HP]
17 Mizzou - University of Missouri [Columbia]
18 Sidra Medicine [Doha, Qatar]
19 Children's Hospital of Michigan
20 CMU - Central Michigan University
21 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Solveig Heide
- Fonction : Auteur
- PersonId : 1012475
- ORCID : 0000-0002-4673-9762
- IdRef : 18988438X
J. Austin Hamm
- Fonction : Auteur
Isabelle Schrauwen
- Fonction : Auteur
- PersonId : 1229427
- ORCID : 0000-0001-7310-6082
Résumé
Background Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. Methods Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2- related neurodevelopmental disorder. Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. Conclusion We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.
Domaines
Sciences du Vivant [q-bio]Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Delineating the genotypic and phenotypic spectrum of <i>HECW2</i>-related neurodevelopmental disorders
|
Résumé |
en
Background Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. Methods Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2- related neurodevelopmental disorder. Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. Conclusion We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.
|
Auteur(s) |
Anushree Acharya
1
, Haluk Kavus
2
, Patrick Dunn
3
, Abdul Nasir
4
, Leandra Folk
5
, Kara Withrow
5
, Ingrid M Wentzensen
5
, Maura R Z Ruzhnikov
6
, Camille Fallot
7
, Thomas Smol
8, 7, 9
, Mélanie Rama
7, 9
, Kathleen Brown
10
, Sandra Whalen
11, 12
, Alban Ziegler
13
, Magali Barth
13
, Anna Chassevent
14
, Constance Smith-Hicks
15
, Alexandra Afenjar
11, 12
, Thomas Courtin
16
, Solveig Heide
16, 12
, Esperanza Font-Montgomery
17
, Caleb Heid
17
, J. Austin Hamm
, Donald R Love
18
, Farouq Thabet
18
, Vinod K Misra
19, 20
, Mitch Cunningham
19
, Suzanne M Leal
1
, Irma Jarvela
21
, Elizabeth A Normand
5
, Fanggeng Zou
5
, Mayada Helal
2
, Boris Keren
16
, Erin Torti
5
, Wendy K Chung
2
, Isabelle Schrauwen
1
1
CUMC -
Columbia University Medical Center
( 177495 )
- Columbia University Medical Center, Black Building 1613, 630 West 168th Street, New York, NY 10032
- États-Unis
2
Columbia University [New York]
( 75524 )
- Columbia University in the City of New York, 2960 Broadway, New York, NY 10027-6902
- États-Unis
3
GW -
The George Washington University
( 304728 )
- 2121 Eye Street, NW , Washington, DC 20052
- États-Unis
4
University of Agriculture Faisalabad - UAF (PAKISTAN)
( 303379 )
-
- France
5
GeneDx [Gaithersburg, MD, USA]
( 536296 )
- 207 Perry Parkway
Gaithersburg, MD 20877
- États-Unis
6
Stanford University
( 73500 )
- 450 Serra Mall, Stanford, CA 94305-2004
- États-Unis
7
CHRU Lille -
Centre Hospitalier Régional Universitaire [CHU Lille]
( 425779 )
- CHU/CHRU Lille - 2, avenue Oscar Lambret - 59037 Lille Cedex
- France
8
RADEME -
Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
( 497295 )
- Clinique de Génétique médicale Guy Fontaine -
Centre de référence maladies rares Anomalies du développement -
Hôpital Jeanne de Flandre -
59037 Lille Cedex.
- France
9
Institut de génétique médicale
( 302256 )
-
- France
10
University of Colorado Anschutz [Aurora]
( 558492 )
- https://www.cuanschutz.edu/
University of Colorado Anschutz Medical Campus
- États-Unis
11
CHU Trousseau [APHP]
( 360410 )
- 26 Avenue du Dr Arnold Netter, 75012 Paris
- France
12
SU -
Sorbonne Université
( 413221 )
- 21 rue de l’École de médecine - 75006 Paris
- France
13
CHU Angers -
Centre Hospitalier Universitaire d'Angers
( 151939 )
- 4 rue Larrey - 49933 Angers cedex 9
- France
14
Kennedy Krieger Institute [Baltimore]
( 519828 )
- Baltimore, Maryland, United States
- États-Unis
15
Johns Hopkins University School of Medicine [Baltimore]
( 148207 )
- 733 North Broadway, Suite G49
Baltimore, MD 21205-2196
- États-Unis
16
CHU Pitié-Salpêtrière [AP-HP]
( 353778 )
- 47-83 Boulevard de l'Hôpital, 75013 Paris
- France
17
Mizzou -
University of Missouri [Columbia]
( 136087 )
- 230 Jesse Hall | Columbia, MO 65211
- États-Unis
18
Sidra Medicine [Doha, Qatar]
( 534573 )
- Al Gharrafa Street, Ar-Rayyan, Doha
- Qatar
19
Children's Hospital of Michigan
( 308153 )
- États-Unis
20
CMU -
Central Michigan University
( 368038 )
- 200 S. Franklin St. • Mount Pleasant, Mich. 48859
- États-Unis
21
Helsingin yliopisto = Helsingfors universitet = University of Helsinki
( 50895 )
- Yliopistonkatu 4, 00100 Helsinki
- Finlande
|
Langue du document |
Anglais
|
Nom de la revue |
|
Date de publication |
2021-07-28
|
Volume |
59
|
Numéro |
7
|
Page/Identifiant |
669 - 677
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Domaine(s) |
|
Mots-clés |
en
genetic variation, human genetics, neurology, phenotype
|
DOI | 10.1136/jmedgenet-2021-107871 |
Pubmed Id | 34321324 |
Origine :
Fichiers produits par l'(les) auteur(s)
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