LAUSR

A 26-year-old Caucasian female was referred for new onset nephrotic syndrome (NS). She was well until early June 2018 when she developed bilateral leg swelling followed by swelling of her arms and face. About 2 weeks into her leg swelling she was seen by nephrology who noted peripheral edema, a serum creatinine of 1.1 mg/dl (CKD-EPI eGFR 69), a serum albumin of 2.7 gm/dl and a urine protein creatinine ratio (UPC) of 9 (Table 1). Her prior serum creatinine was 0.7 mg/dl in 2014. She was diagnosed with NS and started on furosemide. She underwent a kidney biopsy that showed focal and segmental glomerulosclerosis (FSGS) in 2 out of 47 glomeruli with focal mild interstitial fibrosis and tubular atrophy, and severe diffuse foot process effacement (FPE) on EM (see Fig. 1a–c). She was started on lisinopril and was referred to the Renal Genetics Clinic because of her reluctance to start prednisone. A 3-generation pedigree demonstrated that she has no family history of kidney disease (Fig. 2). Clinical examination showed that she has no extrarenal features, such as nail or patella abnormalities or hearing loss to suggest a syndromic form of FSGS. After meeting with a genetic counselor, she underwent genetic screening with KidneySeqTM, a customized targeted renal gene panel [1]. Testing showed that she had a heterozygous missense variant in Transient Receptor Potential Cation Channel subfamily C Member 6 (TRPC6), a gene where pathogenic variants are a known cause of autosomal dominant FSGS [2] Fig. 1, panel D). The variant, p.Asn125Ser, the consequence of a c.374A > G transition is rare, is predicted to be deleterious, and in a previous study this variant demonstrated increased calcium transients in transfected HEK293 cells compared to the wild type gene (Supplementary reference 21). Furthermore, the variant has been previously reported in an adult with sporadic FSGS and in two siblings with childhood onset steroid resistant nephrotic syndrome (SRNS) (Supplementary reference 9, 21). Based on American College of Medical Genetics (ACMG) criteria (PS3, PP2, PP3, PP5, BS2), the variant was labeled as likely pathogenic (Supplementary reference 18). She was diagnosed with autosomal dominant FSGS, and based on prior reports of FSGS-TRPC6 disease she was advised that corticosteroids were likely to be ineffective (Supplementary reference 20, 21). While continuing lisinopril with furosemide as needed, her peripheral edema improved, her proteinuria resolved, and her serum albumin normalized (Table 1). 2 years after initial presentation she continues to do well with a normal UPC ratio. Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s4062 0-020-00837 -7) contains supplementary material, which is available to authorized users.