Background: Autosomal polycystic kidney disease is distinguished into dominant
(ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic
(PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are
genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD)
in adults. Additionally, exemptions from dominant and recessive inheritance have been
reported in both disorders resulting in respective phenocopies. Here, we comparatively
report three young adults with microcystic-hyperechogenic kidney morphology based
on unexpected genetic alterations beyond typical inheritance.
Methods: Next-generation sequencing (NGS)-based gene panel analysis and multiplex
ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial
segregation analysis, and reverse phenotyping.
Results: Three unrelated individuals presented in late adolescence for differential
diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and
liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1
missense variant causing pseudodominant inheritance in a family, a large monoallelic
PKDH1-deletion with atypical transmission, and biallelic PKD1 missense hypomorphs
with recessive inheritance.
Conclusion: By this report, we illustrate clinical presentations associated with atypical
PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic
PKHD1-alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may
lead to mild CKD in the absence of prominent macrocyst formation and functional
liver impairment. The long-term renal prognosis throughout life, however, remains
undetermined. Increased detection of atypical inheritance challenges our current
thinking of disease ontology not only in PKD but also in Mendelian disorders in general.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84286 |
| Date | 24 March 2023 |
| Creators | de Fallois, Jonathan, Schönauer, Ria, Münch, Johannes, Nagel, Mato, Popp, Bernt, Halbritter, Jan |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1664-8021, 682565 |
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