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. 2024 Mar 28;12(2):101280.
doi: 10.1016/j.gendis.2024.101280. eCollection 2025 Mar.

Expanding the spectrum of novel candidate genes using trio exome sequencing and identification of monogenic cause in 27.5% of 320 families with steroid-resistant nephrotic syndrome

Ronen Schneider  1 , Shirlee Shril  1 , Florian Buerger  1 , Konstantin Deutsch  1 , Kirollos Yousef  1 , Camille N Frank  1 , Ana C Onuchic-Whitford  1   2 , Thomas M Kitzler  1 , Youying Mao  1 , Verena Klämbt  1 , Muhammad Y Zahoor  1   3 , Katharina Lemberg  1 , Amar J Majmundar  1 , Bshara Mansour  1 , Ken Saida  1 , Steve Seltzsam  1 , Caroline M Kolvenbach  1   4 , Lea Maria Merz  1   5 , Nils D Mertens  1 , Tobias Hermle  1 , Nina Mann  1 , Dalia Pantel  1   6 , Abdul A Halawi  1 , Aaron Bao  1 , Luca Schierbaum  1 , Sophia Schneider  1 , Daanya Salmanullah  1 , Iddo Z Ben-Dov  7 , Itamar Sagiv  7 , Loai A Eid  8 , Hazem Subhi H Awad  8 , Muna Al Saffar  1   9 , Neveen A Soliman  10   11 , Marwa M Nabhan  12   13 , Jameela A Kari  12   13 , Sherif El Desoky  12   13 , Mohamed A Shalaby  12   13 , Said Ooda  14 , Hanan M Fathy  15 , Shrikant Mane  16 , Richard P Lifton  16 , Michael J G Somers  1 , Friedhelm Hildebrandt  1
Affiliations

Expanding the spectrum of novel candidate genes using trio exome sequencing and identification of monogenic cause in 27.5% of 320 families with steroid-resistant nephrotic syndrome

Ronen Schneider et al. Genes Dis. .
No abstract available

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Figures

Figure 1
Figure 1
Exome sequencing analysis results in 320 families with SRNS. (A) In 88 of 320 (27.5%) families with SRNS, a likely causative variant was detected in one of 27 genes known to cause SRNS if mutated (blue). In 5.6% of families, a likely causative variant was found in genes causing a kidney disease that may represent phenocopies of SRNS (purple). In 18.1% of families, a variant in one potential novel candidate gene was identified (red), and in 12.5% variants in more than one potential candidate gene were identified, and hence the genetic analysis was inconclusive (green). In 35.6% of families, no causative variants or candidate genes were detected (yellow). In 0.6% of families, a causative gene for a non-nephrotic syndrome kidney disease was detected. (B) The detection rate of likely causative genetic variants in known SRNS genes is dependent on the extent of homozygosity by descent. We examined each family's whole exome sequencing data for the degree of homozygosity by descent (Hildebrandt PLoS Genet 5:p.e1000353, 2019) and defined homozygosity by descent (HBD) to an individual if ≥ 50 Mb of homozygosity were found by mapping. We identified 101/320 (31.5%) families with HBD, in 52 (51.5%) of whom we detected a likely causative variant in an SRNS disease-causing gene. In contrast, in families with <50 Mbp of homozygosity on mapping, a likely causative variant was detected in an SRNS gene in only 36/219 (16.4%). The difference in variant detection between homozygous and non-homozygous families was statistically significant using Fisher's exact test (∗P < 0.001). (C) Potential novel candidate SRNS genes can be detected at a higher rate using “trio-analysis” than “singlet-analysis” in non-homozygous families. In 45 families with homozygosity of ≥50 Mb by mapping for whom no variants were found in either known SRNS or phenocopy genes, we detected novel candidate SRNS genes in 17 out of 33 ″singlets” (51.5%), and in 7/13 (53.8%) by trio/duo analysis (P > 0.05, Fisher Exact Test). In 166 families with homozygosity by mapping of <50 Mb, for whom no variants were found in either known SRNS or phenocopy genes, we detected novel candidate SRNS genes in 17 out of 107 ″singlets” (15.9%), and in 17/59 (28.8%) by trio/duo analysis (∗∗P < 0.05, Fisher Exact Test). Of these, 9 were compound-heterozygously inherited, 2 were heterozygous de novo, and 6 were homozygously inherited variants. SRNS, steroid-resistant nephrotic syndrome.
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References

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