{
  "abstract": "Background & Aims: Laterality disorders are rare congenital conditions caused by disruption of left–right embryonic patterning, often associated with ciliary dysfunction. Despite the identification of numerous causative genes, the molecular basis remains unresolved in many patients. We aimed to identify the genetic cause of left isomerism heterotaxy in two unrelated patients, and investigate the functional consequences of the implicated gene.\n\nMethods: Genome sequencing was performed in both patients. Candidate variants were validated by RNA and protein analyses in patient‐derived fibroblasts. To study the functional consequences, we conducted RNA‐seq, cell cycle assays (flow cytometry, EdU incorporation, Ki‐67 staining), rescue experiments with the wild‐type gene, and primary ciliogenesis studies.\n\nResults: Both patients harboured biallelic loss‐of‐function variants in PIH1D2, a gene not previously associated with human disease. Transcript analyses confirmed aberrant splicing, and immunofluorescence staining revealed loss of PIH1D2 expression in Patient 1's primary fibroblasts. RNA‐seq demonstrated dysregulation of pathways related to cell cycle regulation and developmental signalling. Patient fibroblasts showed impaired cell cycle re‐entry from G0 following serum starvation and reduced S‐phase progression. Wild type PIH1D2 overexpression partially rescued these defects. Furthermore, patient cells exhibited significantly reduced primary ciliogenesis compared to controls.\n\nConclusions: Our findings establish PIH1D2 as a novel disease gene for left isomerism heterotaxy, with biliary atresia observed in one of the patients. Loss of PIH1D2 impairs ciliogenesis and cell cycle progression, providing a mechanistic link between ciliary defects and abnormal left–right patterning. These results expand the spectrum of cilia‐related laterality disorders and identify PIH1D2 as a critical regulator of human development.",
  "abstract_shown": true,
  "affiliations": [
    "The Genetics Institute and Genomics Center Tel Aviv Sourasky University Medical Center Tel Aviv Israel",
    "Gray Faculty of Medical and Health Sciences Tel Aviv University Tel Aviv Israel",
    "The Simon Winter Institute for Human Genetics Bnai Zion Medical Center Haifa Israel",
    "Ruth and Bruce Rappaport Faculty of Medicine Technion—Israel Institute of Technology Haifa Israel",
    "Pediatric Gastroenterology Unit Hillel Yaffe Medical Center Hadera Israel",
    "Pediatric Pulmonology, Children's Hospital University of Duisburg‐Essen Essen Germany",
    "Institute of Human Genetics Galilee Medical Center Nahariya Israel",
    "The Genetics Institute Rambam Health Care Campus Haifa Israel",
    "Clinical Genetics Austin Health Melbourne Australia",
    "Department of Pediatric Surgery, Ruth Rappaport Children's Hospital Rambam Health Care Campus Haifa Israel",
    "Neonatal Intensive Care Unit Hillel Yaffe Medical Center Hadera Israel",
    "Department of Human Genetics Hannover Medical School Hannover Germany",
    "Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) German Center for Lung Research (DZL) Hannover Germany",
    "Community Genetics, Public Health Services Ministry of Health Jerusalem Israel"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Alina Kurolap",
      "orcid": "0000-0002-7005-3621"
    },
    {
      "affs": [
        0
      ],
      "name": "Chofit Chai Gadot"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Adel Shalata"
    },
    {
      "affs": [
        4
      ],
      "name": "Orly Eshach Adiv"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yam Amir",
      "orcid": "0000-0002-4900-6345"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Bar Levy Lando"
    },
    {
      "affs": [
        5
      ],
      "name": "Florian Stehling",
      "orcid": "0000-0002-2417-2048"
    },
    {
      "affs": [
        6
      ],
      "name": "Tova Hershkovitz",
      "orcid": "0009-0008-1755-003X"
    },
    {
      "affs": [
        2
      ],
      "name": "Khaled Osman"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Clair Habib"
    },
    {
      "affs": [
        2
      ],
      "name": "Hila Mintz"
    },
    {
      "affs": [
        3,
        9
      ],
      "name": "Ran Steinberg"
    },
    {
      "affs": [
        10
      ],
      "name": "Amit Hochberg"
    },
    {
      "affs": [
        0
      ],
      "name": "Uri Hamiel",
      "orcid": "0000-0001-8983-464X"
    },
    {
      "affs": [
        0
      ],
      "name": "Adi Mory"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Daphna Marom",
      "orcid": "0000-0003-2107-9646"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "Sandra von Hardenberg",
      "orcid": "0000-0002-3680-7450"
    },
    {
      "affs": [
        13
      ],
      "name": "Amihood Singer"
    },
    {
      "affs": [
        11
      ],
      "name": "Bernd Auber",
      "orcid": "0000-0003-1880-291X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hagit Baris Feldman",
      "orcid": "0000-0003-4065-7560"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c87dtknvvfc04.bib",
  "cited_by": 0,
  "doi": "10.1111/liv.70951",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13714337/",
  "id": "c87dtknvvfc04",
  "issns": [
    "1478-3223",
    "1478-3231"
  ],
  "landing_url": "https://doi.org/10.1111/liv.70951",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "1311|Genetic and Kidney Cyst Diseases"
    ]
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  "openalex": "W7224105957",
  "pdf_url": "https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/liv.70951",
  "pmcid": "PMC13714337",
  "pmid": "42947407",
  "published": "2026-10-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c87dtknvvfc04.ris",
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    {
      "first_seen": "2026-11-01T12:21:51Z",
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      "field": "biology",
      "origin": "openalex:1311|Genetic and Kidney Cyst Diseases",
      "subfield": "genetics-genomics"
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  ],
  "title": "PIH1D2 Loss‐of‐Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia",
  "title_text": "PIH1D2 Loss‐of‐Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:51Z",
  "url": "https://research.draconitic.com/paper/c87dtknvvfc04",
  "venue": "Liver International",
  "versions": []
}