Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia

Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia Publisher Pubmed

Barish S^{1, 25} ; Lin SJ² ; Maroofian R³ ; Gezdirici A⁴ ; Alhebby H⁵ ; Trimouille A^{6, 7} ; Waberski MB⁸ ; Mitani T¹ ; Huber I⁹ ; Tveten K¹⁰ ; Holla OL¹⁰ ; Busk OL¹⁰ ; Houlden H³ ; Karimiani EG¹¹ Show All Authors

Barish S^{1, 25}
Lin SJ²
Maroofian R³
Gezdirici A⁴
Alhebby H⁵
Trimouille A^{6, 7}
Waberski MB⁸
Mitani T¹
Huber I⁹
Tveten K¹⁰
Holla OL¹⁰
Busk OL¹⁰
Houlden H³
Karimiani EG¹¹
Toosi MB¹²
Badv RS¹³
Torbati PN¹⁴
Eghbal F¹⁴
Akhondian J¹²
Al Safar A^{15, 16}
Alswaid A¹⁷
Zifarelli G¹⁸
Bauer P¹⁸
Marafi D^{1, 19}
Fatih JM¹
Huang K²
Petree C²
Calame DG^{1, 20, 21}
Von Der Lippe C¹⁰
Alkuraya FS²²
Wali S⁵
Lupski JR^{1, 21, 23, 24}
Varshney GK²
Posey JE¹
Pehlivan D^{1, 20, 21}

Show Affiliations

1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, United States
2. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, 73104, OK, United States
3. Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
4. Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul, 34480, Turkey
5. Division of Gastroenterology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
6. Department of Medical, Genetics, University Hospital of Bordeaux, Bordeaux, 33076, France
7. INSERM U1211, Laboratoire Maladies Rares: Genetique, et Metabolisme, Bordeaux University
8. Inova Health System, Falls Church, VA, United States
9. Department of Pediatrics, Sorlandet Hospital, Arendal, Norway
10. Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway
11. Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom
12. Neuroscience Research Center, Mashhad University of Medical Science, Mashhad, Iran
13. Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences
14. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
15. College of Medicine, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
16. Department of Paediatrics, King Fahd Hospital of University, Al-khobar, Saudi Arabia
17. King Saud Bin Abdulaziz University for Health Sciences, Department of Pediatrics, MC 1940, King Abdullah Specialized Children's Hospital, Riyadh, Saudi Arabia
18. CENTOGENE GmbH, Am Strande 7, Rostock, 18055, Germany
19. Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat, 13110, Kuwait
20. Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, 77030, TX, United States
21. Texas Children's Hospital, Houston, 77030, TX, United States
22. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
23. The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
24. Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
25. Colossal Biosciences, Dallas, 75247, TX, United States

Source: American Journal of Human Genetics Published:2024

Abstract

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of NDD, dysmorphic features, and liver dysfunction. Using family-based rare variant analyses of exome sequencing (ES) data and case matching through GeneMatcher, we describe the clinical phenotypes of 11 additional individuals in eight unrelated families (nine unrelated families, 14 individuals in total) with biallelic putative truncating variants in WDR83OS. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Whereas bile acids were significantly elevated in 5/6 of individuals tested, bilirubin was normal and liver enzymes were normal to mildly elevated in all 14 individuals. In three of six individuals for whom longitudinal data were available, we observed a progressive reduction in relative head circumference. A zebrafish model lacking Wdr83os function further supports its role in the nervous system, craniofacial development, and lipid absorption. Taken together, our data support a disease-gene association between biallelic loss-of-function of WDR83OS and a neurological disease trait with hypercholanemia. © 2024 American Society of Human Genetics

2. Novel Variants Broaden the Phenotypic Spectrum of Plekhg5-Associated Neuropathies, European Journal of Neurology (2021)

3. A Comprehensive Overview of Nf1 Mutations in Iranian Patients, NeuroMolecular Medicine (2024)

4. Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome, Journal of Clinical Investigation (2020)

5. Whole-Genome Sequencing Reveals Host Factors Underlying Critical Covid-19, Nature (2022)

6. Genome-Wide Association Study of Long Covid, Nature Genetics (2025)

7. Bi-Allelic Loss of Function Variant in the Nrcam Gene Is Associated With Motor-Predominant Axonal Polyneuropathy; the Second Report, Molecular Genetics and Genomic Medicine (2023)

Experts (# of related papers)

View all Related Experts

Rasoul Aliannejad (2)

Ahmadreza Niavarani (2)

Style	Citing Format
MLA	Barish S, et al.. "Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia." American Journal of Human Genetics, vol. 111, no. 11, 2024, pp. 2566-2581.
APA	Barish S, Lin SJ, Maroofian R, Gezdirici A, Alhebby H, Trimouille A, Waberski MB, Mitani T, Huber I, Tveten K, Holla OL, Busk OL, Houlden H, Karimiani EG, Toosi MB, Badv RS, Torbati PN, Eghbal F, Akhondian J, ... Pehlivan D (2024). Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia. American Journal of Human Genetics, 111(11), 2566-2581.
Chicago	Barish S, Lin SJ, Maroofian R, Gezdirici A, Alhebby H, Trimouille A, Waberski MB, et al.. "Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia." American Journal of Human Genetics 111, no. 11 (2024): 2566-2581.
Harvard	Barish S et al. (2024) 'Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia', American Journal of Human Genetics, 111(11), pp. 2566-2581.
Vancouver	Barish S, Lin SJ, Maroofian R, Gezdirici A, Alhebby H, Trimouille A, et al.. Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia. American Journal of Human Genetics. 2024;111(11):2566-2581.
BibTex	@article{ author = {Barish S and Lin SJ and Maroofian R and Gezdirici A and Alhebby H and Trimouille A and Waberski MB and Mitani T and Huber I and Tveten K and Holla OL and Busk OL and Houlden H and Karimiani EG and Toosi MB and Badv RS and Torbati PN and Eghbal F and Akhondian J and Al Safar A and Alswaid A and Zifarelli G and Bauer P and Marafi D and Fatih JM and Huang K and Petree C and Calame DG and Von Der Lippe C and Alkuraya FS and Wali S and Lupski JR and Varshney GK and Posey JE and Pehlivan D}, title = {Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia}, journal = {American Journal of Human Genetics}, volume = {111}, number = {11}, pages = {2566-2581}, year = {2024} }
RIS	TY - JOUR AU - Barish S AU - Lin SJ AU - Maroofian R AU - Gezdirici A AU - Alhebby H AU - Trimouille A AU - Waberski MB AU - Mitani T AU - Huber I AU - Tveten K AU - Holla OL AU - Busk OL AU - Houlden H AU - Karimiani EG AU - Toosi MB AU - Badv RS AU - Torbati PN AU - Eghbal F AU - Akhondian J AU - Al Safar A AU - Alswaid A AU - Zifarelli G AU - Bauer P AU - Marafi D AU - Fatih JM AU - Huang K AU - Petree C AU - Calame DG AU - Von Der Lippe C AU - Alkuraya FS AU - Wali S AU - Lupski JR AU - Varshney GK AU - Posey JE AU - Pehlivan D TI - Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia JO - American Journal of Human Genetics VL - 111 IS - 11 SP - 2566 EP - 2581 PY - 2024 ER -

Science Communicator Platform

Authors

Authors Affiliations

Abstract