Clinical features and genetic analysis of a child with Progressive familial intrahepatic cholestasis type 5 due to variant of NR1H4 gene

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Introduction: Progressive familial intrahepatic cholestasis (PFIC) type 1 and type 2, characterized by normal serum gamma-glutamyltransferase levels, are caused by defects in FIC1 and BSEP, respectively. Previous reports showed that PFIC type 1 patients had bland intracanalicular cholestasis, whereas non-type 1 patients were marked by non-specific giant cell hepatitis with moderately to markedly elevated serum transaminase levels. However, there has been only one study comparing the clinical features of these two genotypes on the basis of a molecular diagnosis. To investigate the occurrence of genetic mutations and clinical differences between the two genotypes, we performed mutational analysis in FIC1 and BSEP genes in patients with PFIC phenotypes and normal gamma-glutamyltransferase activities. Methods: The coding region and exonintron boundaries of the FIC1 and BSEP gene were sequenced in 17 unrelated Japanese PFIC patients with normal serum gamma-glutamyltransferase activities. All patients were Japanese, from various parts of the country. The following clinical data were collected: age at onset, clinical signs of cholestasis, serum alanine aminotransferase (ALT) levels, liver histology, growth, and therapy including liver transplantation. Results: All patients had novel disease-causing mutations in FIC1 or BSEP. Of the 17 patients, 13 carried FIC1 mutations (5 homozygotes, 7 compound heterozygotes, 1 heterozygote), and 4 carried BSEP mutations (1 homozygote, 2 compound heterozygotes, 1 heterozygote). FIC1 mutations included 8 missense mutations, 2 nonsense mutations, 2 insertions, 1 deletion and 3 splicing mutations. BSEP mutations consisted of 5 missense mutations and 1 exon skipping. There were overlap in ALT levels between PFIC type 1 and PFIC type 2 patients, and other clinicopathological features were insufficient to differentiate between the two genotypes. However, complications such as intractable diarrhea or severe liver steatosis occurred after transplantation in 12 of the 13 patients with type 1, while they never occurred in the type 2 patients. Conclusion: PFIC type 1 is the major type in Japan, and frequently causes severe complications such as intractable diarrhea and liver steatosis after liver transplantation. For predicting these unfavorable complications, genetic diagnosis is needed for case of PFIC before liver transplantation, because it is impossible to distinguish between PFIC type 1 and PFIC type 2 by clinical findings exclusively.

To explore the clinical phenotype and genetic characteristics of a child with Progressive familial intrahepatic cholestasis type 8 (PFIC8). METHODS A child with PFIC diagnosed at Beijing Children's Hospital Affiliated to Capital Medical University in September 2025 was selected as the study subject. Peripheral venous blood samples were collected from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variants were validated by Sanger sequencing. The pathogenicity of the candidate variants was classified based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Beijing Children's Hospital Affiliated to Capital Medical University (Ethics No.: 2023-E-126-Y). The proband, a 2-month-old female infant, had manifested jaundice of the skin and sclera, and slightly distended abdomen. She had no visible abdominal wall varicose veins, soft abdomen, and no palpable masses. Biliary atresia was ruled out by intraoperative cholangiography. WES revealed that she has harbored compound heterozygous variants of KIF12 gene, namely c.809C>T (p.Ala270Val) and c.1313G>A (p.Arg438Lys), which were verified by Sanger sequencing to have derived from her mother and father, respectively. According to the ACMG guidelines, both variants were classified as variants of uncertain significance (VUS). Based on the pre-defined search strategy, 10 articles were retrieved, which involved 25 PFIC cases, including 5 from China. Together with the proband of this study, the 26 PFIC patients have primarily presented with high GGT cholestasis, with the genetic cause in all cases attributed to variants of the KIF12 gene. The c.809C>T and c.1313G>A compound heterozygous variants of the KIF12 gene probably underlay the pathogenesis of cholestatic liver disease in this child. Above findings have enriched the mutational and phenotypic spectra of PFIC8.

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To explore the clinical manifestation and genotype of a child with Progressive familial intrahepatic cholestasis 8 (PFIC8) due to variant of KIF12 gene. A child diangosed with PFIC8 at Changzhou Children's Hospital in October 2017 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples (3 mL each) were collected from the patient, her parents and younger sister. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variants were validated using Sanger sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was classified. This study has been approved by the Medical Ethics Committee of Changzhou Children's Hospital (Ethics No.: 2023-002). The main clinical manifestations of the child included high GGT cholestasis, portal hypertension, splenomegaly, and abnormal liver enzymes. WES revealed that she has harbored compound heterozygous variants of the KIF12 gene, namely c.245G >A (p.Arg82Gln) and c.1291del (p.Ser431Valfs*13). Bioinformatics analyses showed that both variants were pathogenic. A total of 25 cases were reported in 7 English literature, including 13 males and 12 females. All patients had presented with high GGT cholestasis. Some had progressed to cirrhosis, and 3 cases also had renal lesions. No death was reported. Six children were treated with LTx. Nineteen children were found to harbor homozygous variants of the KIF12 gene, and the remaining six harbored compound heterozygous variants of the same gene. The most common mutation was c.655C>T (p.Arg219*). The mutation sites are mainly located in the Kinesin motor catalytic domain, with high GGT cholestasis as the main clinical feature. No correlation was found between the genotype and phenotype. PFIC8 caused by KIF12 deficiency is mainly characterized by high GGT cholestasis, for which there is no effective treatment. The c.245G>A and c.1291del compound heterozygous variants of the KIF12 gene probably underlay the pathogenesis in this child.

The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

American society of human genetics updates guidance on genetic testing in children: Group addresses predictive genetic testing, use of secondary findings from genomic sequencing tests.

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Background. Cholestatic liver diseases represent a pressing issue in modern pediatric gastroenterology. They significantly impact the quality of life of both children and their families, often lead to disability and high mortality rates, and are a primary indication for liver transplantation. In pediatric practice, various liver diseases can manifest with cholestasis, a pathological process characterized by impaired bile synthesis or flow, leading to the accumulation of bile components (bile acids, bilirubin, cholesterol) in the body and progressive damage to liver tissue. This pathological condition can be caused by anatomical obstructions, developmental anomalies of the biliary tract structures, infections of various etiologies, metabolic diseases, or genetically determined defects in enzymatic and transport systems. Objective. The purpose of this study is to provide a clinical example of a rare genetic disorder, progressive familial intrahepatic cholestasis type 3 (PFIC-3). These defects disrupt the processes of bile acid synthesis and excretion and cause damage to hepatocytes and epithelial cells of the bile ducts. One rare genetic pathology is Progressive Familial Intrahepatic Cholestasis type 3. This is an autosomal recessive disease caused by defects in the ABCB4 gene, which encodes the MDR3 transport protein responsible for phospholipid secretion into bile. The disease manifests in early childhood and is characterized by progressive cholestasis, intense pruritus, failure to thrive, and a high risk of developing liver cirrhosis. Diagnosing Progressive Familial Intrahepatic Cholestasis type 3 presents significant challenges due to the absence of pathognomonic clinical signs and requires the use of molecular genetic methods for verification. Conclusion. The article presents a clinical case of Progressive Familial Intrahepatic Cholestasis type 3 in a girl, diagnosed at the age of 1 year and 6 months, with a confirmed homozygous mutation c.2534G>T in the ABCB4 gene. For the first time in Russian practice, the experience of using odevixibat – a selective inhibitor of the intestinal bile acid transporter (IBAT) – in this category of patients is described.

NEWS updateN oninvasive prenatal tests used to screen for trisomies 13, 18, and 21 have specific advantages and limitations that should be thoroughly explained to pregnant women so they can carefully consider this option, according to a recent policy statement from the American College of Medical Genetics and Genomics (ACMG).The recommendation from ACMG is the fifth guidance statement about these tests, which are marketed in the U.S. by four companies.It follows statements from the American College of Obstetricians and Gynecologists (ACOG)/Society for Maternal-Fetal Medicine (SMFM), two from the International Society for Prenatal Diagnosis (ISPD), and the National Society of Genetic Counselors (NSGC).While the ACMG generally agrees with advice from these other groups, their statement makes important departures.Namely, the ACMG calls these tests-which detect cell-free fetal DNA (cfDNA) in maternal blood-"noninvasive prenatal screening" (NIPS) tests to emphasize that they are not diagnostic.Likewise, the ACMG statement places no limits on who should be offered NIPS and goes into greater detail about what patients should know about it [Gregg et al., 2013]."ACMG's statement emphasizes that NIPS is a screening test, not the be-all and end-all.There are certain caveats with [these] tests," says