The expanding phenotypic spectra of kidney diseases: insights from genetic studies

Stokman, Marijn; Renkema, Kirsten Y.; Giles, Rachel; Schaefer, Franz; Knoers, Nine V A M; Eerde, Albertien M. van

doi:10.1038/nrneph.2016.87

Cited by 70 publications

(86 citation statements)

References 156 publications

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“…Some heterozygous mutations in COL4A3 and COL4A4 genes can cause a milder phenotype, defined as thin basement membrane nephropathy (TBMN; MIM#141200, or benign familial hematuria), which is characterized by persistent microscopic hematuria although rarely combined with progressive proteinuria and end-stage renal disease [4]. …”

Section: Introductionmentioning

confidence: 99%

Alport syndrome cold cases: Missing mutations identified by exome sequencing and functional analysis

et al. 2017

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Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. Despite simultaneous screening of these genes being widely available, mutation detection still remains incomplete in a non-marginal portion of patients. Here, we applied whole-exome sequencing (WES) in 3 Italian families negative after candidate-gene analyses. In Family 1, we identified a novel heterozygous intronic variant (c.2245-40A>G) -outside the conventionally screened candidate region for diagnosis- potentially disrupting COL4A5 exon29 splicing. Using a minigene-based approach in HEK293 cells we demonstrated that this variant abolishes exon29 branch site, causing exon skipping. Moreover, skewed X-inactivation of the c.2245-40A>G allele correlated with disease severity in heterozygous females. In Family 2, WES highlighted a novel COL4A5 hemizygous missense mutation (p.Gly491Asp), which segregates with the phenotype and impacts on a highly-conserved residue. Finally, in Family 3, we detected a homozygous 24-bp in-frame deletion in COL4A3 exon1 (NM_000091.4:c.30_53del:p.Val11_Leu18del or c.40_63del24:p.Leu14_Leu21del), which is ambiguously annotated in databases, although it corresponds to a recurrent AS mutation. Functional analyses showed that this deletion disrupts COL4A3 signal peptide, possibly altering protein secretion. In conclusion, WES -together with functional studies- was fundamental for molecular diagnosis in 3 AS families, highlighting pathogenic variants that escaped previous screenings.

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Section: Introductionmentioning

confidence: 99%

Alport syndrome cold cases: Missing mutations identified by exome sequencing and functional analysis

et al. 2017

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“…One mother showed focal segmental glomerulosclerosis (FSGS) on kidney biopsy. Presentation of Alport syndrome with isolated proteinuria [17] and FSGS in male and female patients [18][19][20][21] have been reported before. The etiology of FSGS may be that it develops secondary to the abnormalities in the GBM, or alternatively that FSGS belongs to a spectrum of diseases of the GBM primarily caused by a COL4A3-5 mutation.…”

Section: Discussionmentioning

confidence: 99%

Diagnosing Alport Syndrome: Lessons from the Pediatric Ward

Vos

Zietse

Geel

et al. 2018

Nephron

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Background: Alport syndrome is a rare inheritable kidney disease frequently leading to end-stage kidney disease in young adults. Patients could benefit from early recognition of the disease. In several children with Alport syndrome, a parent was noticed to have renal symptoms attributed to another renal disease. Aim: To review the renal history of the closest family members of a cohort of pediatric patients with genetically proven Alport syndrome. Methods: The medical records of all children with genetically proven Alport syndrome identified at our pediatric nephrology department in the last 20 years were reviewed, with focus on the medical history of affected parents. Results: Twenty-three children with Alport syndrome from 21 different families were identified. Eight of 21 probands had family member(s) with renal symptoms attributed to other diseases. In these, a type IV collagen mutation was determined only after the manifestation of Alport syndrome in their child. One proband presented atypically with acute membrano-proliferative glomerulo-nephritis. Only 3 out of 8 probands with a known family history of Alport syndrome had been intentionally screened for this disease. A COL4A5 mutation was found in 18 probands, COL4A3 in 2, and COL4A4 in 1. Each family showed private mutations; 17 out of 21 mutations were novel. Conclusions: Atypical presentation of Alport syndrome was quite common in mothers of our pediatric patients. To enable earlier diagnosis of Alport syndrome, nephrologists should look for a positive diagnosis in any patient with persistent renal symptoms, especially if there is a positive family history of (any) renal disease.

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“…Of note, patients with Alport’s syndrome can present with FSGS on kidney biopsy and therefore, this cannot be used as a feature to distinguish between the two conditions [16, 17]. Mutations in the COL4A3-5 genes that encode α-chains of glomerular basement membrane collage type IV are classically associated with Alport’s syndrome, and recent studies have shown that these mutations can be associated with FSGS [18]. In our patient, whole exome sequencing did not reveal COL4A3-5 mutations.…”

Section: Discussionmentioning

confidence: 99%

Focal segmental glomerulosclerosis associated with mitochondrial disease

Lim¹,

Steele²,

Fenves³

et al. 2017

CNCS

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Primary mitochondrial diseases (MD) are complex, heterogeneous inherited diseases caused by mutations in either the mitochondrial or nuclear DNA. Glomerular diseases in MD have been reported with tRNA mutation m.3243A>G causing a syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). We describe here a case of focal segmental glomerulosclerosis (FSGS) associated with a new tRNA mutation site. A 34-year-old man with a history of living related kidney transplantation, diabetes, hearing loss, and developmental delay presented to the outpatient clinic with complaints of new behavioral difficulties, worsening symptoms, and brain involvement on imaging. Physical examination was remarkable for difficulty hearing, a pattern of dysarthric speech, and cerebellar gait. Laboratory investigations including lactate levels were unremarkable. Based on this set of clinical circumstances, concern for an underlying genetic abnormality was raised. Multiple metabolic tests were unremarkable. Whole exome sequencing revealed a mitochondrial MT-TW tRNA change at position m.5538G>A. Genotype-phenotype correlations are consistent with this tRNA mutation as a cause of his symptoms. To the best of our knowledge, this is the first case describing FSGS-associated MD caused by an m.5538 G>A mutation. Consideration of an underlying MD should be made in patients presenting with deafness, neurologic changes, diabetes, and renal failure.

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The expanding phenotypic spectra of kidney diseases: insights from genetic studies

Cited by 70 publications

References 156 publications

Alport syndrome cold cases: Missing mutations identified by exome sequencing and functional analysis

Alport syndrome cold cases: Missing mutations identified by exome sequencing and functional analysis

Diagnosing Alport Syndrome: Lessons from the Pediatric Ward

Focal segmental glomerulosclerosis associated with mitochondrial disease

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