Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants

Maddirevula, Sateesh; Alhebbi, Hamoud; Al‐Qahtani, Awad; Algoufi, Talal; Alsaif, Hessa S.; Ibrahim, Niema; Abdulwahab, Firdous; Barr, Mohammed; Alzaidan, Hamad; Almehaideb, Ali; AlSasi, Omai; Alhashem, Amal; Hussaini, Hussa Al; Wali, Sami; Alkuraya, Fowzan S.

doi:10.1038/s41436-018-0288-x

Cited by 89 publications

(111 citation statements)

References 37 publications

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“…Lastly, during the final stages of preparation of this manuscript, an independent study was published online describing 4 children from 3 unrelated families with high‐GGT cholestasis of unclear etiology, and no extrahepatic abnormalities who were found to harbor recessive mutations in KIF12. Two of the 4 affected children underwent liver transplantation at 6 years and 10 months of age, respectively . The latter harbors the aforementioned p.Val204Met missense mutation identified in our patients 2.1 and 2.2.…”

Section: Discussionmentioning

confidence: 77%

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

et al. 2019

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Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma‐glutamyltransferase (GGT) cholestasis. Here, we report whole‐exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 ( KIF12 ). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion : Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children.

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Section: Discussionmentioning

confidence: 77%

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

et al. 2019

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“…Recently, seven families with cholestatic liver diseases who were negative for known PFIC mutations underwent whole exome sequencing, leading to the discovery of three new pathogenic variants associated with PFIC‐like presentations. These included USP53 (encodes for a protein that interacts with TJP2 ), LSR (regulator of liver development), and WDR83OS (interacts with bile salt export pump [BSEP]) …”

Section: Pficmentioning

confidence: 99%

“…These included USP53 (encodes for a protein that interacts with TJP2), LSR (regulator of liver development), and WDR83OS (interacts with bile salt export pump [BSEP]). 4 The management of PFIC disease in infancy and childhood focuses on ensuring adequate nutrition in the setting of fat and fat-soluble vitamin malabsorption, controlling the severe pruritus with medications or surgery, and monitoring for cirrhosis and portal hypertension. One option for treating pruritus is the surgical partial external biliary diversion (PEBD), whereby the bile from the gallbladder is diverted to the skin via a loop of jejunum, thus decreasing the systemic pool of bile salts.…”

Section: An Official Learning Resource Of Aasldmentioning

confidence: 99%

Inherited Cholestatic Diseases in the Era of Personalized Medicine

Goldberg

Mack

2020

Clinical Liver Disease

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“…Other independent studies have consistently reported WES diagnostic rates of 20% or higher . Furthermore, we and others have successfully combined WES with deep phenotyping (i.e., detailed characterization of each patient's phenotypic features) to identify the underlying genetic defects in infants and children with idiopathic liver diseases, including children with liver failure of indeterminate etiology . Astute clinical annotation (i.e., comprehensive phenotype description of the patient) is central to harnessing the maximal potential of genomic data .…”

Section: Where Could Hepatologists Be Missing Liver‐related Genetic Tmentioning

confidence: 95%

“…(22)(23)(24)(25) Furthermore, we and others have successfully combined WES with deep phenotyping (i.e., detailed characterization of each patient's phenotypic features) to identify the underlying genetic defects in infants and children with idiopathic liver diseases, including children with liver failure of indeterminate etiology. (18,19,(26)(27)(28)(29)(30)(31)(32) Astute clinical annotation (i.e., comprehensive phenotype description of the patient) is central to harnessing the maximal potential of genomic data. (29,33) Notably, the vast majority of these studies have been performed in pediatric populations and in cancer patients.…”

Section: Where Could Hepatologists Be Missing Liver-related Genetic Tmentioning

confidence: 99%

Exome Sequencing in Clinical Hepatology

Vilarinho¹,

Mistry

2019

Hepatology

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The clinical relevance of the Human Genome Project and next‐generation sequencing technology was demonstrated for the first time in 2009, when whole‐exome sequencing (WES) provided the definitive diagnosis of congenital chloride diarrhea in an infant with presumed renal salt‐wasting disease. Over the past decade, numerous studies have shown the utility of WES for clinical diagnosis as well as for discovery of novel genetic disorders through analysis of a single or a handful of informative pedigrees. Hence, advances in improving the speed, accuracy, and computational analysis combined with exponential decrease in the cost of sequencing the human genome is transforming the practice of medicine. The impact of WES has been most noticeable in pediatric disorders and oncology, but its utility in the liver clinic is recently emerging. Here, we assess the current status of WES for clinical diagnosis and acceleration of translation research to enhance care of patients with liver disease.

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Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants

Cited by 89 publications

References 37 publications

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

Inherited Cholestatic Diseases in the Era of Personalized Medicine

Exome Sequencing in Clinical Hepatology

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