Table 1.

Continued

Familya	A Priori Clinical Diagnosis	Post-WES Diagnosis	Extrarenal Manifestations	Family History	Homozygosity (>75 MB)	Gene	Zygosity	c.Change p.Change Segregation (m, p)b	Conservation	PP2c SIFTd/MutationTastere	Allele Frequency in gnomADf	HGMDg (ACMGh)	PMID (if previously reported)
ESRD of unknown etiology
B797	ESRD	NPHP	Learning disability, cerebellar hypoplasia	No	Yes	NPHP1	Hom	Homozygous deletion (NA)				Variant (P)	#9326933
B238	ESRD	SRNS	None	No	Yes	NUP93	Hom	c.575A>G	X.t.	0.03 Del/DC	0/7/282,600	Gene (LP)	Novel
								p.Y192C (NA)
B2559	ESRD	SRNS	None	No	No	TRPC6	Het	c.2684G>T	D.r.	0.90 Del/DC	None	Variant (P)	#21734084
								p.R895L (WT, WT)
B1873	ESRD	NPHP	Neonatal stroke, mild autism spectrum disorder	No	No	TTC21B	Cpd het	c.986A>T	C.i.	0.99 Del/DC	0/1/251,074	Gene (LP)
								p.E329V (het, WT)m					Novel
								c.1038G>A	N/A	N/A	None	Gene (P)	Novel
								p.W346* (WT, WT)m

Patients are grouped according to their a priori clinical diagnosis. The patients in whom WES clarified the clinical diagnosis or lead to a diagnosis for the first time are underlined. m, p, maternal allele, paternal allele; ACMG, American College of Medical Genetics and Genomics; PMID, PubMed ID; NA, not available; L, left; UPJO, ureteropelvic junction obstruction; R, right; MCDK, multicystic dysplastic kidney; RCAD, renal cysts and diabetes; BOR, branchio-oto-renal syndrome; Het, heterozygous; P, pathogenic; C.i., Ciona intestinalis; Tol, tolerated (SIFT); DC, disease causing (MutationTaster); B/L, bilateral; C.e., Caenorhabditis elegans; Del, deleterious (SIFT); LP, likely pathogenic; VUR, vesicoureteral reflux; ADHD, attention deficient hyperactivity disorder; D.m., Drosophila melanogaster; VSD, ventricular septal defect; EEC, ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome; pat gpa, paternal grandfather; H.s., Homo sapiens; CNS, congenital nephrotic syndrome; Cpd het, compound heterozygous; Hemi, hemizygous; Hom, homozygous; D.r., Danio rerio; M.m., Mus musculus; Poly, polymorphism (MutationTaster); NPHP, nephronophthisis; WT, wild type; G.g., Gallus gallus; ARPKD, autosomal recessive polycystic kidney disease; X.t., Xenopus tropicalis; S.c., Saccharomyces cerevisiae.

^aFamily number is underlined: WES altered or further clarified the a priori clinical diagnosis.

^bSegregation listed as (maternal allele, paternal allele). If maternal and paternal DNA are unavailable, segregation is listed as NA.

^cPolyPhen-2 score, which predicts potential effect of an amino acid change on the structure and function of a protein (http://genetics.bwh.harvard.edu/pph2). More deleterious mutations are closer to 1.000, whereas tolerant changes are closer to 0.000.

^dSIFT, which predicts whether an amino acid change will affect protein function (http://sift.bii.a-star.edu.sg/).

^eMutationTaster, prediction tool to determine deleteriousness of an amino acid substitution (http://www.mutationtaster.org).

^fGenome Aggregation Database (gnomAD; http://www.gnomad.broadinstitute.org).

^gHuman Gene Mutation Database (HGMD; https://portal.biobase-international.com), listed as “Variant” if mutation is reported in HGMD or “Gene” if gene, but not specific allele is reported.

^hACMG classifications as described previously.³¹

ⁱProband underwent clinical genetic testing before enrollment in this study. Mutation was confirmed via WES.

^jProband underwent panel sequencing previously in our laboratory before enrollment in this study. Mutation was confirmed via WES.

^kProbands with compound heterozygous mutations in whom parental DNA was unavailable for segregation. These were only considered to be molecularly solved if there was a clear genotype-phenotype correlation.

^lIndex case published previously (PMID 24882706).

^mInspection of WES reads demonstrate that the two alleles are in trans (Supplemental Figure 5).