Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression

Sabrina Giglio; Aldesia Provenzano; Benedetta Mazzinghi; Francesca Becherucci; Laura Giunti; Giulia Sansavini; Fiammetta Ravaglia; Rosa Maria Roperto; Silvia Farsetti; Elisa Benetti; Mario Rotondi; Luisa Murer; Elena Lazzeri; Laura Lasagni; Marco Materassi; Paola Romagnani

doi:10.1681/ASN.2013111155

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Figure 1.
Flow diagram showing mechanisms for filtering variants to identify the variants of potential pathogenicity. AA, amino acid; HGMD, Human Gene Mutation Database; ins/del, insertion/deletion; MAF, minor allele frequency; NHLBI, National Heart, Lung, and Blood Institute; snp, single nucleotide polymorphism.
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Figure 2.
Analysis of patients’ genotypes in relation to age at onset of nephrotic syndrome and response to treatments. (A) Percentage of mutations in patients with SRNS or SSNS. Patients with mutated SRNS are represented in white, and patients with not mutated SRNS are represented in gray. Patients with SSNS are represented in the striped column. (B) Age at onset in patients affected by nephrotic syndrome. Patients with SRNS are classified as mutated (white box) or not mutated (gray box); Patients with SSNS are represented in the striped box. In each box, the bottom and top of the box are always the first and third quartiles, and the band inside the box is always the second quartile (the median). Squares inside each box represent the mean value for each group. The whiskers indicate variability outside the upper and lower quartiles, with the end of the whiskers representing fifth and 95th percentiles. Triangles represent first and 99th percentiles in each box. (C) Percentage of FSGS, minimal change disease (MCD), and diffuse mesangial sclerosis (DMS) pathologic findings in patients with mutated SRNS (white column) versus not mutated SRNS (gray column). (D) Percentage of responders to immunosuppressive treatment (IS) in patients with mutated SRNS (white column), not mutated SRNS (gray column), and SSNS (striped column). *P<0.05; **P<0.001.

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Table 1.

Potentially pathogenic variants identified in the patients included in the study

Samples	Potentially Pathogenic Variants	State of Variants	Inheritance	Refs.	Prediction of Pathogenicity of Variants
					In Silico Analysis		AA Conservation among Species
					PolyPhen	PMut	AA Conservation among Species
Patient 1	NPHS2 c.[-52C>G]+[-52C>G]	Homozygous	AR	Oleggini et al.¹⁶
Patient 2	NPHS2 c.[419delG]+[419delG]; p.[Gly140Aspfs41]+[Gly140Aspfs41]	Homozygous	AR	Boute et al.¹⁷
Patient 3	NPHS2 c.[413G>A]+[467_468insT]; p.[Arg138Gln]+[Leu156Phefs*11]	Compound heterozygous	AR	Boute et al.¹⁷; Caridi et al.¹⁸
Patient 4	NPHS2 c.[104insG]+[1143delC]; p.[Gly35Glyfs35]+[Pro381Profs5]	Compound heterozygous	AR	Boute et al.¹⁷; Berdeli et al.¹⁹
Patient 5	NPHS2 c. [771C>T]+[911C>T]; p.[Arg229Gln]+[Ser304Phe]	Compound heterozygous	AR	Tsukaguchi et al.²⁰	Pos dam	Path	++^a
Patient 6	PLCE1 c.[4570_4571delAT]+[2277G>T]; p.[Met1524Alafs*5]+[Arg548Leu]	Compound heterozygous	AR		Prob dam	Path	+++^b
Patient 7	PLCE1 c.[2038C>T]+[4327G>A]; p.[Gln680*]+[Gly1443Arg]	Compound heterozygous	AR		Prob dam	Path	+++^b
Patient 8	ACTN4 c.[782C>A]+[=]; p.[Val261Glu]+[=]	Heterozygous	AD		Prob dam	Path	+++^b
Patient 9	ACTN4 c.[464T>C]+[=]; p.[Ile155Thr]+[=]	Heterozygous	AD		Prob dam	Neu	+++^b
Patient 10	LMX1B c.[833C>T]+[=]; p.[Ala278Val]+[=]	Heterozygous	AD		Prob dam	Path	+++^b

AR, autosomal recessive; AD, autosomal dominant; Pos dam, possibly damaging; Path, pathologic; Prob dam, probably damaging; Neu, neutral; AA, amino acid.
↵a Medium conservation.
↵b High conservation.