Title: A NOVEL SALL1 VARIANT IN TOWNES-BROCKS SYNDROME ASSOCIATED WITH ADULT-ONSET RENAL FAILURE

The SALL1 gene encodes a crucial transcription factor (Spalt-like transcription factors) involved in chromatin remodelling and thus gene expression during development of limbs, kidneys, ears and other organs. Variants that impact its function cause a variety of clinical pathology including Townes-Brocks syndrome type 1 and TB branchio-oto-renal-like syndrome, usually associated with structural kidney deformities in children. These conditions are inherited in an autosomal dominant pattern in families.

A 24-year-old male was investigated for chronic renal impairment, creatinine 160 µmol/L, eGFR 51ml/min/1.73^2, with historical readings between 120-130umol for up to 10 years. Urine studies showed no haematuria and mild proteinuria with an albumin to creatinine ratio of 18mg/mmol. Renal imaging showed no scarring, cysts or obstruction and kidneys were 103mm and 97mm in size. A glomerulonephritis screen was unremarkable. There was a strong family history of renal disease, including his father with stage 3a chronic kidney disease and paternal family members with end stage kidney disease. Kidney biopsy showed no significant abnormalities on light microscopy and negative immunofluorescence. Electron microscopy demonstrated widespread (>75%) foot process effacement consistent with focal segmental glomerulosclerosis (FSGS). Genetic testing with standard glomerular and tubulointerstitial gene panels were negative. 

Due to the strong family history, he was formally reviewed by the genetics service. Suggestive features within his family history included some individuals with adult-onset sensorineural hearing loss, although this did not always segregate with the chronic renal impairment. Broad thumbs and halluces, and other subtle digital anomalies were noted in the proband and his affected father.  Broader genetic testing was conducted, in the form of a trio Kidneyome super panel (patient and parents), to interrogate the known monogenic syndromes associated with kidney failure, using exome sequencing. This identified a heterozygous loss-of-function variant, c.598del, in the SALL1gene. This variant has not been described in population databases or in the literature This variant is a single base deletion (frameshift) which is predicted to create a premature stop codon and result in a null allele. Based on ACMG guidelines, this variant has been classified as likely pathogenic. This variant was also present in the patient’s affected father with hearing loss, digital anomalies and adult-onset renal failure.

This case aims to highlight a novel SALL1 variant associated with Townes-Brocks syndrome (TBS). This family lacks the typical congenital anomalies associated with TBS. In this family. the novel variant is presenting primarily with adult-onset renal impairment and variable hearing loss, with subtle digital anomalies.  In this case there is histopathological correlation with an FSGS picture, which has been rarely reported in TBS, rather than the typical congenital abnormalities of the kidney and urinary tract (CAKUT) such as hypo-dysplasia, cystic kidneys or unilateral absent kidney. The biopsy finding of FSGS can be a cause to trial immunosuppressive treatment, however this case demonstrates the importance of pursuing early diagnostic genetic testing in those with a strong family history of renal failure to prevent unnecessary immunosuppression exposure.