Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature

Abstract

Townes-Brocks syndrome (TBS, MIM#107480) is an autosomal dominant disorder linked to SALL1 alterations and characterized by a clinical triad (anorectal, thumb, and external-ear malformations), along with variable features. Renal failure and deafness can occur at any age, making follow-up essential. Some genotype-phenotype correlations have been suggested but data are limited. We collected clinical and molecular data from 49 patients with a SALL1 (likely) pathogenic variant identified in our laboratory or through collaborations, and reviewed the 207 SALL1 related-TBS patients previously reported in the literature. We performed statistical analysis to study genotype-phenotype correlations based notably on the variant position in relation to the glutamine-rich region. In our series, 25% of individuals presented with the clinical triad compared to 49.7% in the literature. The deafness frequency was similar (65%). Renal failure was diagnosed in 39.6% of our patients compared to 29.3% in the literature. Developmental delay or intellectual disability affected 9% of patients. Of the 22 SALL1 variants in our series, 35% were located upstream of the glutamine-rich region, compared to 6.5% in the literature. Statistical analysis was performed on all patients, of which 26 and 200 carried a variant upstream and downstream of the glutamine-rich region, respectively. A significant increase in deafness, dysplastic ear, and thumb malformations and a significant decrease in renal failure were observed in the individuals carrying a variant located downstream of the region, but the patients were significantly younger. Future studies should aim to elucidate the complex pathophysiological mechanisms and prognosis of TBS, functionally and prospectively.

Fig. 1. Ear dysplasia and limb malformations in 18 patients from 12 families in the present series.

Ear dysplasia consisted mainly of abnormally folded helix and auricular tag or pit (arrow) (patient F20P40 was considered unaffected for ear dysplasia). Upper limb malformations mainly included triphalangeal thumb (patients F1P1, F5P9, F6P10, F6P13, F13P26, F18P32, F18P34, F19P36), duplicated thumb (patients F4P7, F5P9, F6P13, F9P16, F18P32, F18P34, F20O47), broad thumb (patients F4P8 and F20P47) (patients F6P12 and F8P15 were considered unaffected for upper limb malformations).

Fig. 2. Pedigrees of 4 families in the present series.

The first row refers to the four main signs: thumb features (preaxial polydactyly (PPD)/triphalangeal thumb (TT)/other thumb abnormality (OT)), anorectal malformation (AM), ear dysplasia (ED) and hearing loss (HL). The clinical triad is underlined when present. The numbers refer to the patient numbers given in Table S1, where the clinical and molecular characteristics are detailed. *No external abnormalities; cardiac and renal examinations were not performed. DD, developmental delay; del, deletion; dup, duplication; ID, intellectual disability; inv, inversion; IUGR, intra-uterine growth retardation.

Fig. 3. Schematic representation of the truncating variants and deletion of SALL1 gene from the present series.

All variants were located in exon 2. Fifty-two percent (11/21) of variants were located in the mutation hot-spot defined by Botzenhart et al. in 2007 [4]. Nineteen percent (4/21) of variants were located upstream or within the glutamine-rich region [4, 12], and 72.5% (29/40) of variants were located upstream of the middle of the mutation hotspot [4]. Three variants (bold) have been reported in other families in the literature [21, 25, 26]. The deletion involved SALL1 and HNRPNA1L3 genes.