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Comprehensive genetic testing in children with a clinical diagnosis of ARPKD identifies phenocopies

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Abstract

Background

Autosomal recessive polycystic kidney disease (ARPKD) is genetically one of the least heterogeneous ciliopathies, resulting primarily from mutations of PKHD1. Nevertheless, 13–20% of patients diagnosed with ARPKD are found not to carry PKHD1 mutations by sequencing. Here, we assess whether PKHD1 copy number variations or second locus mutations explain these cases.

Methods

Thirty-six unrelated patients with the clinical diagnosis of ARPKD were screened for PKHD1 point mutations and copy number variations. Patients without biallelic mutations were re-evaluated and screened for second locus mutations targeted by the phenotype, followed, if negative, by clinical exome sequencing.

Results

Twenty-eight patients (78%) carried PKHD1 point mutations, three of whom on only one allele. Two of the three patients harbored in trans either a duplication of exons 33–35 or a large deletion involving exons 1–55. All eight patients without PKHD1 mutations (22%) harbored mutations in other genes (PKD1 (n = 2), HNF1B (n = 3), NPHP1, TMEM67, PKD1/TSC2). Perinatal respiratory failure, a kidney length > +4SD and early-onset hypertension increase the likelihood of PKHD1-associated ARPKD. A patient compound heterozygous for a second and a last exon truncating PKHD1 mutation (p.Gly4013Alafs*25) presented with a moderate phenotype, indicating that fibrocystin is partially functional in the absence of its C-terminal 62 amino acids.

Conclusions

We found all ARPKD cases without PKHD1 point mutations to be phenocopies, and none to be explained by biallelic PKHD1 copy number variations. Screening for copy number variations is recommended in patients with a heterozygous point mutation.

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Funding

This work was supported by OTKA K109076 and Ministry of National Economy, Hungary GINOP-2.3.2-15-2016-00039 (to István Balogh, Zoltán Maróti and Tibor Kalmár), MTA-SE Lendulet Research Grant (LP2015-11/2015) of the Hungarian Academy of Sciences and NKFIA/OTKA K109718, KH125566 (to Kálmán Tory).

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  1. Tamás Szabó and Petronella Orosz equally contributed to this work

Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Tamás Szabó, Petronella Orosz & György Balla

  2. Ist Department of Pediatrics, Semmelweis University Budapest, Bókay J. u. 53., Budapest, 1083, Hungary

    Petronella Orosz, Eszter Balogh, Eszter Jávorszky, István Máttyus, Attila J Szabó, George Reusz, Ildikó Várkonyi & Kálmán Tory

  3. MTA-SE Lendulet Nephrogenetic Laboratory, Budapest, Hungary

    Eszter Balogh, Eszter Jávorszky & Kálmán Tory

  4. Department of Pediatrics, University of Szeged, Szeged, Hungary

    Csaba Bereczki, Zoltán Maróti & Tibor Kalmár

  5. MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary

    Attila J Szabó

  6. Department of Pediatrics, Szabolcs-Szatmár-Bereg Jósa András County Hospital, Nyíregyháza, Hungary

    Erzsébet Marián

  7. Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Nagyerdei krt. 98., Debrecen, Hungary

    Éva Gombos, Orsolya Orosz, László Madar, János Kappelmayer & István Balogh

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  1. Tamás Szabó
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  2. Petronella Orosz
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  4. Eszter Jávorszky
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  9. Attila J Szabó
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  18. Kálmán Tory
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Correspondence to Kálmán Tory or István Balogh.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Parents and patients gave informed written consent.

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Szabó, T., Orosz, P., Balogh, E. et al. Comprehensive genetic testing in children with a clinical diagnosis of ARPKD identifies phenocopies. Pediatr Nephrol 33, 1713–1721 (2018). https://doi.org/10.1007/s00467-018-3992-5

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  • DOI: https://doi.org/10.1007/s00467-018-3992-5

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