SLC35A2‐CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals
Bobby Ng
(1)
,
Paulina Sosicka
(1)
,
Satish Agadi
(2, 3)
,
Mohammed Almannai
(2, 3)
,
Carlos Bacino
(2, 3)
,
Rita Barone
(4)
,
Lorenzo Botto
(5)
,
Jennifer Burton
(6)
,
Colleen Carlston
(5)
,
Brian Hon-Yin Chung
(7)
,
Julie Cohen
(8)
,
David Coman
,
Katrina Dipple
(9, 10)
,
Naghmeh Dorrani
(11)
,
William Dobyns
(12)
,
Abdallah Elias
,
Leon Epstein
(13)
,
William Gahl
(14)
,
Domenico Garozzo
(4)
,
Trine Bjørg Hammer
,
Jaclyn Haven
,
Delphine Héron
(15, 16)
,
Matthew Herzog
(11)
,
George Hoganson
(6)
,
Jesse Hunter
(9)
,
Mahim Jain
(17)
,
Jane Juusola
(18)
,
Shenela Lakhani
(19)
,
Hane Lee
(20)
,
Joy Lee
(21)
,
Katherine Lewis
(18)
,
Nicola Longo
(5)
,
Charles Marques Lourenço
,
Christopher Mak
(7)
,
Dianalee Mcknight
(18)
,
Bryce Mendelsohn
(22)
,
Cyril Mignot
(15, 16)
,
Ghayda Mirzaa
,
Wendy Mitchell
,
Hiltrud Muhle
,
Stanley Nelson
,
Mariusz Olczak
,
Christina Palmer
,
Arthur Partikian
,
Marc Patterson
,
Tyler Pierson
,
Shane Quinonez
,
Brigid Regan
,
M Elizabeth Ross
,
Maria Guillen Sacoto
,
Fernando Scaglia
,
Ingrid Scheffer
,
Devorah Segal
,
Nilika Shah Singhal
,
Pasquale Striano
,
Luisa Sturiale
,
Joseph Symonds
,
Sha Tang
,
Eric Vilain
,
Mary Willis
,
Lynne Wolfe
,
Hui Yang
,
Shoji Yano
,
Zöe Powis
,
Sharon Suchy
,
Jill Rosenfeld
,
Andrew Edmondson
,
Stephanie Grunewald
,
Hudson Freeze
1
Sanford Burnham Prebys Medical Discovery Institute
2 BCM - Baylor College of Medicine
3 Texas Children's Hospital [Houston, USA]
4 Unict - Università degli studi di Catania = University of Catania
5 University of Utah
6 University of Illinois College of Medicine
7 HKU Med - LKS Faculty of Medicine
8 Kennedy Krieger Institute [Baltimore]
9 University of Washington [Seattle]
10 Seattle Children’s Hospital
11 UCLA - University of California [Los Angeles]
12 Center for Integrative Brain Research
13 Feinberg School of Medicine
14 NHGRI - National Human Genome Research Institute
15 CHU Pitié-Salpêtrière [AP-HP]
16 ICM - Institut du Cerveau = Paris Brain Institute
17 University of Melbourne
18 UC San Francisco - University of California [San Francisco]
19 Ambry Genetics [Aliso Viejo, CA, USA]
20 GeneDx [Gaithersburg, MD, USA]
21 Center for neurogenetics [Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York]
22 Children’s Hospital Los Angeles [Los Angeles]
2 BCM - Baylor College of Medicine
3 Texas Children's Hospital [Houston, USA]
4 Unict - Università degli studi di Catania = University of Catania
5 University of Utah
6 University of Illinois College of Medicine
7 HKU Med - LKS Faculty of Medicine
8 Kennedy Krieger Institute [Baltimore]
9 University of Washington [Seattle]
10 Seattle Children’s Hospital
11 UCLA - University of California [Los Angeles]
12 Center for Integrative Brain Research
13 Feinberg School of Medicine
14 NHGRI - National Human Genome Research Institute
15 CHU Pitié-Salpêtrière [AP-HP]
16 ICM - Institut du Cerveau = Paris Brain Institute
17 University of Melbourne
18 UC San Francisco - University of California [San Francisco]
19 Ambry Genetics [Aliso Viejo, CA, USA]
20 GeneDx [Gaithersburg, MD, USA]
21 Center for neurogenetics [Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York]
22 Children’s Hospital Los Angeles [Los Angeles]
David Coman
- Fonction : Auteur
Abdallah Elias
- Fonction : Auteur
Trine Bjørg Hammer
- Fonction : Auteur
Jaclyn Haven
- Fonction : Auteur
Charles Marques Lourenço
- Fonction : Auteur
Ghayda Mirzaa
- Fonction : Auteur
Wendy Mitchell
- Fonction : Auteur
Hiltrud Muhle
- Fonction : Auteur
Stanley Nelson
- Fonction : Auteur
Mariusz Olczak
- Fonction : Auteur
Christina Palmer
- Fonction : Auteur
Arthur Partikian
- Fonction : Auteur
Marc Patterson
- Fonction : Auteur
Tyler Pierson
- Fonction : Auteur
Shane Quinonez
- Fonction : Auteur
Brigid Regan
- Fonction : Auteur
M Elizabeth Ross
- Fonction : Auteur
Maria Guillen Sacoto
- Fonction : Auteur
Fernando Scaglia
- Fonction : Auteur
Ingrid Scheffer
- Fonction : Auteur
Devorah Segal
- Fonction : Auteur
Nilika Shah Singhal
- Fonction : Auteur
Pasquale Striano
- Fonction : Auteur
Luisa Sturiale
- Fonction : Auteur
Joseph Symonds
- Fonction : Auteur
Sha Tang
- Fonction : Auteur
Eric Vilain
- Fonction : Auteur
Mary Willis
- Fonction : Auteur
Lynne Wolfe
- Fonction : Auteur
Hui Yang
- Fonction : Auteur
Shoji Yano
- Fonction : Auteur
Zöe Powis
- Fonction : Auteur
Sharon Suchy
- Fonction : Auteur
Jill Rosenfeld
- Fonction : Auteur
Andrew Edmondson
- Fonction : Auteur
Stephanie Grunewald
- Fonction : Auteur
Hudson Freeze
- Fonction : Auteur
Résumé
Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.