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Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis

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Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis BRIEF COMMUNICATION www.jasn.org Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis † †‡ ‡ Jan Halbritter,* Michelle Baum,* Ann Marie Hynes, Sarah J. Rice, David T. Thwaites, Zoran S. Gucev,§ Brittany Fisher,* Leslie Spaneas,* Jonathan D. Porath,* Daniela A. Braun,* | † Ari J. Wassner, Caleb P. Nelson,¶ Velibor Tasic,§ John A. Sayer, and Friedhelm Hildebrandt*** *Division of Nephrology, Department of Medicine, |Division of Endocrinology, Department of Medicine, and ¶Department of Urology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts; †Institute of Genetic Medicine, International Centre for Life and ‡Epithelial Research Group, Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; §Medical Faculty Skopje, University Children’s Hospital, Skopje, Macedonia; and **Howard Hughes Medical Institute, Chevy Chase, Maryland ABSTRACT Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of the overall population of stone formers. monogenic causes have been identified, the fraction of single-gene disease has not been Furthermore, absence of a positive family well studied. To determine the percentage of cases that can be molecularly explained by history, which will be the rule in recessive mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput genes and may be frequent in dominant mutation analysis in a cohort of consecutively recruited patients from typical kidney stone genes with incomplete penetrance, often clinics. The cohort comprised 272 genetically unresolved individuals (106 children and leads to the false assumption that a mono- 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis genic cause is unlikely. We, therefore, (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading hypothesized that monogenic causes of to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations NL/NC account for a high percentage of were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The stone formers. For most individuals with percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric NL/NC, mutation analysis for a causative cohorts (20.8%). Recessive causes were more frequent among children, whereas domi- geneticdefect has notbeen accessibleso far. nant disease occurred more abundantly in adults. Our study provides an in-depth analysis With the advent of massively parallel se- of monogenic causes of kidney stone disease. We suggest that knowledge of the mo- quencing techniques and high-throughput lecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and library preparation, mutation analysis of might facilitate personalized treatment. multiple genes in large cohorts has not only become technically feasible but also, J Am Soc Nephrol 26: 543–551, 2015. doi: 10.1681/ASN.2014040388 cost-effective.7 To determine the percentage of mono- genic causes in kidney stone disease, we Nephrolithiasis (NL) is a highly prevalent autosomal-dominant, autosomal-recessive, 5,6 condition affecting up to 10% of individ- or X-linked transmission. The ability Received April 18, 2014. Accepted June 18, 2014. uals in the Western world.1 It is associated to detect the causative mutation(s) in a fi Published online ahead of print. Publication date with signi cant morbidity because of col- monogenic disease gene is of great diagnos- available at www.jasn.org. icky pain, the necessity of surgical proce- tic and potentially therapeutic importance, dures, and progression to CKD.2 NL and because there is an almost deterministic Correspondence: Dr.JohnA.Sayer,Instituteof – Genetic Medicine, International Centre for Life, related conditions, such as nephrocalci- cause effect relationship in monogenic Newcastle University, Central Parkway, Newcastle nosis (NC), share a well recognized heri- disease. upon Tyne NE1 3BZ, UK, or Prof. Friedhelm Hildebrandt, tability, emphasized by the fact that up to However, the contribution of mono- Division of Nephrology, Boston Children’sHospital,300 Longwood Avenue, Boston, MA 02115. Email: john. two thirds of hypercalciuric stone formers genic disorders to the overall prevalence of [email protected] or friedhelm.hildebrandt@ have relatives with NL.3–5 There are at NL has never been studied comprehen- childrens.harvard.edu least 30 genes that have been shown to sively. Hence, data are lacking on the Copyright © 2015 by the American Society of cause single-gene forms of NL/NC by frequency of monogenic forms of NL in Nephrology J Am Soc Nephrol 26: 543–551, 2015 ISSN : 1046-6673/2603-543 543 544 Table 1. Twenty-nine molecular diagnoses established in six dominant genes in a cohort of 272 individuals (268 families) with NL/NC BRIEF COMMUNICATION Clinical Genetic Practical Implication Gene/ Nucleotide Amino Acid Evolutionary Age of Stone State PPh2 Ref. Diagnosis Diagnosis (Because of Genetic Individual Change Change Conservation Onset (yr) Analysis Journal of the American Society of Nephrology (Prescreening) (Postscreening) Diagnosis) SLC7A9 B208–21 c.313G.A p.Gly105Arg Het 0.998 D. melanog. 9 1 Cystine CU+NL ► CU, type B — JAS-C8a c.313G.A p.Gly105Arg Het 0.998 D. melanog. 9 17 CaOx Idiopathic NL ► CU, type B Quantify urinary cystine JAS-E5 c.313G.A p.Gly105Arg Het 0.998 D. melanog. 9 17 Ca CU+NL/NC ► CU, type B Hydration and urinary alkalinization F1029–21a,b c.313G.A p.Gly105Arg Het 0.998 D. melanog. 9 6 ND Idiopathic NC ► CU, type B Quantify urinary cystine, www.jasn.org c.544G.A p.Ala182Thr Het 0.056 D. melanog. 10 hydration, and urinary alkalinization JAS-D30 c.313G.A p.Gly105Arg Het 0.998 D. melanog. 9 25 Cystine CU+NL ► CU, type B — c.614del p.Lys205Argfs*59 Het ——Novel JAS-D31 c.411_412del p.Pro139Leufs*69 Het ——10 28 Cystine CU+NL ► CU, type B — JAS-D47 c.411_412del p.Pro139Leufs*69 Het ——10 45 Cystine CU+NL ► CU, type B — JAS-D34 c.411_412del p.Pro139Leufs*69 Het ——10 35 Cystine CU+NL ► CU, type B — JAS-D28 c.544G.A p.Ala182Thr Hom 0.056 D. melanog. 10 30 Cystine CU+NL ► CU, type B — JAS-F41a c.544G.A p.Ala182Thr Het 0.056 D. melanog. 10 60 ND HC+NL ► CU, type B Quantify urinary cystine JAS-F50a c.544G.A p.Ala182Thr Het 0.056 D. melanog. 10 50 ND Idiopathic NL ► CU, type B Quantify urinary cystine JAS-D57 c.544G.A p.Ala182Thr Het 0.056 D. melanog. 10 7 Cystine CU+NL ► CU, type B — c.614dup p.Asn206Glufs*3 Het ——11 JAS-F87a c.614dup p.Asn206Glufs*3 Het ——11 19 CaPO HC+NL ► CU, type B Quantify urinary cystine JAS-G10 c.614dup p.Asn206Glufs*3 Het ——11 43 Cystine CU+NL ► CU, type B — JAS-D29 c.671C.T p.Ala224Val Hom 0.999 S. cerevisae 12 15 Cystine CU+NL ► CU, type B — JAS-D55 c.671C.T p.Ala224Val Het 0.999 S. cerevisae 12 26 Cystine CU+NL ► CU, type B — JAS-F19a c.671C.T p.Ala224Val Het 0.999 S. cerevisae 12 28 ND HC+NL ► CU, type B Quantify urinary cystine c.1369T.C p.Tyr457His Het 0.059 D. rerio Novel B114–21 c.814del p.Val272Cysfs*6 Het ——13 6 Cystine CU+NL ► CU, type B — c.997C.T p.Arg333Trp Het 0.999 D. melanog. 14 JAS-E9 c.1353C.A p.Tyr451* Het ——Novel 26 Cystine CU+NL ► CU, type B — c.1400–2A.G39 splice Het ——Novel ADCY10 JAS-F8 c.1263C.A p.Tyr421* Het ——Novel 10 ND Idiopathic HC ► Idiopathic HC Monitor urinary Ca JAS-F68 c.1282G.A p.Asp428Asn Het 0.996 C. intestinalis Novel 50 CaOx Idiopathic HC+NC ► Idiopathic HC Monitor urinary Ca J Am Soc Nephrol JAS-F29 c.4477del p.Leu1493Serfs*24 Het ——Novel 40 ND Idiopathic NL ► Idiopathic HC Monitor urinary Ca SLC2A9 B179–21a c.1343C.T p.Pro448Leu Het 0.997 D. melanog. Novel 6 ND Idiopathic NL ► RHUC2 Recheck serum/urinary uric acid B230–21a c.1419+1G.A59 splice Het — — Novel 7 ND Idiopathic HC+NL ► RHUC2 Recheck serum/urinary 26: uric acid 543 – 551, 2015 J Am Soc Nephrol Table 1. Continued Clinical Genetic Practical Implication Gene/ Nucleotide Amino Acid Evolutionary Age of Stone State PPh2 Ref. Diagnosis Diagnosis (Because of Genetic Individual Change Change Conservation Onset (yr) Analysis (Prescreening) (Postscreening) Diagnosis) 26: SLC9A3R1 543 B224–21a c.673G.A p.Glu225Lys Het 0.816 D. rerio 15 5 ND Idiopathic HC+NL ► NPHLOP2 Screen family members at risk, – 551, 2015 prevention of bone disease (osteoporosis/fractures) B109–21a c.888+2T.C59 splice site Het ——Novel 17 ND Idiopathic NL ► NPHLOP2 Screen family members at risk, prevention of bone disease (osteoporosis/fractures) SLC22A12 JAS-F98 c.431T.C p.Leu144Pro Het 0.999 S. cerevisae Novel 25 CaOx HU+NL ► RHUC1 — B155–12a c.1300C.T p.Arg434Cys Het 0.235 D. melanog. 16 17 Ca Idiopathic NL ► RHUC1 Recheck serum/urinary uric acid SLC4A1 JAS-E8 c.2716G.C p.Glu906Gln Het 0.597 D. rerio Novel 29 ND HC+NC ► Primary dRTA Correct acidosis PPh2, Polyphen2–HumVar (http://genetics.bwh.harvard.edu/pph2/); Het, heterozygous; D. melanog., Drosophila melanogaster; CU, cystinuria; CaOx, calcium oxalate; CaPO, calcium phosphate; Hom, homozygous; ND, no data; HC, hypercalciuria; S. cerevisae, Saccharomyces cerevisae; D. rerio, Danio rerio; C. intestinalis, Ciona intestinalis; RHUC2, renal hypouricemia type 2; NPHLOP2, hypophosphatemic nephrolithiasis/osteoporosis-2; HU, hypouricemia; RHUC1, renal hypouricemia type 1; dRTA, distal renal tubular acidosis. aMolecular genetic diagnosis added new aspects to the previously established clinical diagnosis (11 of 29=37.9%). bFor individual F1029–21, both heterozygous mutations are on the same allele. www.jasn.org developed.
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