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

Szabó, Tamás; Orosz, Petronella; Balogh, Eszter; Jávorszky, Eszter; Máttyus, István; Bereczki, Csaba; Maróti, Zoltán; Kalmár, Tibor; Szabó, Attila; Reusz, György; Várkonyi, Ildikó; Marián, Erzsébet; Gombos, Eva C.; Orosz, Orsolya; Madar, László; Balla, György; Kappelmayer, János; Tory, Kálmán; Balogh, I

doi:10.1007/s00467-018-3992-5

Cited by 29 publications

(19 citation statements)

References 42 publications

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“…However, hepatic fibrosis is usually not detected prenatally and cannot be used in making the diagnosis. In cases with no detectable mutations, a thorough sequencing has identified phenocopies involving other genes in 20% of these cases . This is of utmost importance regarding prenatal diagnosis and preimplantation diagnosis for the parents' future reproductive plans and points towards the importance in performing WES/WGS when sequencing the PKD1 and PKHD1 genes fails to identify a mutation.…”

Section: Discussionmentioning

confidence: 99%

Prenatal detection of isolated bilateral hyperechogenic kidneys: Etiologies and outcomes

et al. 2019

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Objectives To delineate the etiology and outcome of prenatally diagnosed isolated bilateral hyperechogenic kidneys (IBHK). Study Design Pregnancies with IBHK on prenatal ultrasound identified and followed by us between January 1, 2000 and January 1, 2015 were evaluated regarding the etiology and outcome by evaluation of family history, targeted AR‐PKD and AD‐PKD DNA analysis, and microarray analysis, according to renal size and amniotic fluid volume. Results Of the 52 identified cases, there were 34 cases with enlarged kidneys, 16 with normal size kidneys, and two with small kidneys. There were seven cases with AD‐PKD, six inherited, and one with de novo causative variants in the PKD1 gene. Fifteen had AR‐PKD, and microarray analysis showed two inherited findings: one with 17q12 deletion including the HNF1B/TCF2 gene inherited from asymptomatic mother and a duplication at 3p26.1 inherited from a healthy father. Of the remaining four cases, three cases had bilateral multicystic dysplastic kidneys, and one had unilateral renal agenesis. Conclusion Microarray analysis and mutation analysis for PKD1 and PKHD1 have an important contribution to the diagnostic investigation of IBHK and to the management of affected and future pregnancies. Poor outcome was associated with large hyperechoic kidneys with oligohydramnios.

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Section: Discussionmentioning

confidence: 99%

Prenatal detection of isolated bilateral hyperechogenic kidneys: Etiologies and outcomes

et al. 2019

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“…8,9 Moreover, mutations in several other genes can produce a phenocopy of ARPKD ("see Differential Diagnosis"). 10,11 Clinical Course…”

Section: Etiology and Prevalencementioning

confidence: 99%

“…Variants are often novel and unique to single families in "nonisolated" populations. 11,15,[36][37][38][39] In ARPKD, genotype-phenotype correlations depend on types of mutations. The most severely affected patients typically have two truncating mutations, while patients with milder phenotype have two missense or a missense and a truncating change.…”

Section: Other Clinical Aspectsmentioning

confidence: 99%

Autosomal Recessive Polycystic Kidney Disease—The Clinical Aspects and Diagnostic Challenges

2020

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Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common ciliopathies with kidney (nephromegaly, hypertension, renal dysfunction) and liver involvement (congenital hepatic fibrosis, dilated bile ducts). Clinical features also include growth failure and neurocognitive impairment. Plurality of clinical aspects requires multidisciplinary approach to treatment and care of patients. Until recently, diagnosis was based on clinical criteria. Results of genetic testing show the molecular basis of polycystic kidneys disease is heterogeneous, and differential diagnosis is essential. The aim of the article is to discuss the role of genetic testing and its difficulties in diagnostics of ARPKD in children.

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“…Finally, several phenocopies exist that can lead to a misdiagnosis of ARPKD. A recent study of 36 unrelated patients originally diagnosed with ARPKD but without an identified mutation in PKHD1 found that 22% harbored mutations in other genes including PKD1, HNF1b, NPHP1, TMEM67, and PKD1/TSC2) [45].…”

Section: Genetics-arpkdmentioning

confidence: 99%

Therapies for Childhood Polycystic Kidney Disease

Patil¹,

Sweeney²,

Avner³

2018

obm genet

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Renal cysts are present in a wide variety of hereditary renal diseases in children. The term polycystic kidney disease (PKD) refers to two specific hereditary diseases, distinguished by the usual age of onset and genetic cause: autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF, MIM *606702) and autosomal dominant polycystic disease (ADPKD-OMIM *601313 and OMIM *173910). ARPKD/CHF is characterized by cystic dilations of the renal collecting ducts and developmental defects of biliary ductal plate remodeling, resulting in varying degrees of congenital hepatic fibrosis. ARPKD/CHF is commonly diagnosed in utero or at birth but can remain silent well into adolescence and rarely into adulthood. ADPKD, the most common inherited renal disease is characterized by slow, progressive enlargement of fluid-filled cysts leading to renal failure by the fifth to sixth decade of life in addition to various extrarenal manifestations. ADPKD can manifest in utero, infants, and children and can be a significant cause of morbidity and mortality in this age group. Our understanding of the genetic basis of ARPKD and ADPKD, including mechanisms of transmission and genes involved continues to evolve. Despite

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

Abstract: 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.

Cited by 29 publications

References 42 publications

Prenatal detection of isolated bilateral hyperechogenic kidneys: Etiologies and outcomes

Prenatal detection of isolated bilateral hyperechogenic kidneys: Etiologies and outcomes

Autosomal Recessive Polycystic Kidney Disease—The Clinical Aspects and Diagnostic Challenges

Therapies for Childhood Polycystic Kidney Disease

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