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



Barish S1, 25 ; Lin SJ2 ; Maroofian R3 ; Gezdirici A4 ; Alhebby H5 ; Trimouille A6, 7 ; Waberski MB8 ; Mitani T1 ; Huber I9 ; Tveten K10 ; Holla OL10 ; Busk OL10 ; Houlden H3 ; Karimiani EG11 Show All Authors
Authors
  1. Barish S1, 25
  2. Lin SJ2
  3. Maroofian R3
  4. Gezdirici A4
  5. Alhebby H5
  6. Trimouille A6, 7
  7. Waberski MB8
  8. Mitani T1
  9. Huber I9
  10. Tveten K10
  11. Holla OL10
  12. Busk OL10
  13. Houlden H3
  14. Karimiani EG11
  15. Toosi MB12
  16. Badv RS13
  17. Torbati PN14
  18. Eghbal F14
  19. Akhondian J12
  20. Al Safar A15, 16
  21. Alswaid A17
  22. Zifarelli G18
  23. Bauer P18
  24. Marafi D1, 19
  25. Fatih JM1
  26. Huang K2
  27. Petree C2
  28. Calame DG1, 20, 21
  29. Von Der Lippe C10
  30. Alkuraya FS22
  31. Wali S5
  32. Lupski JR1, 21, 23, 24
  33. Varshney GK2
  34. Posey JE1
  35. Pehlivan D1, 20, 21

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
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