Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

Abstract

Background Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns. Methods A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss. Results Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis. Conclusions This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

A novel SALL1 C757T mutation in a Chinese family causes a rare disease --Townes-Brocks syndrome

“…The third generation (comprising the proband and her sisters) displayed syndactyly of the second and third left toes, and anal abnormalities. This clinical presentation is consistent with findings from previous studies [ 24 ].…”

“…Conversely, clinical manifestations due to haploinsufficiency of SALL1 tend to be relatively mild. ( 22 – 23 ) Furthermore, genetic anticipation has been observed in certain families with Townes-Brocks syndrome, with an increase in clinical severity across generations [ 24 ]. The novel mutations (c.757 C > T p.Gln253* exon2) identified in this study were located in the hotspot mutation region of SALL1 .…”

“…It is worth noting that the clinical variability described in the affected subjects may be linked to different types of variants or to potential epigenetic factors (they may play a more relevant role in case of multiple pregnancies). ( 37 – 38 ) Yang et al [ 24 ] reported a case of a 2-month-old child with Townes-Brocks syndrome (TBS). This patient presented clinical symptoms similar to those observed in our reported case.…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…Knockout mouse studies demonstrated that PTPRQ is an essential component of the stereocilia hair-bundle shaft connectors since deficiency results in hearing loss ( Goodyear et al, 2003 ). In 2010 the formal proof was published that inactivating mutations in the gene are also responsible for deafness in humans ( Schraders et al, 2010 ; Shahin et al, 2010 ) and many more have followed since ( Gao et al, 2015 ; Sang et al, 2015 ; Eisenberger et al, 2018 ; Wu et al, 2018 ; Ozieblo et al, 2019 ; Sang et al, 2019 ; Safka Brozkova et al, 2020 ; Chen et al, 2021a ; Mahmood et al, 2021 ; Yang et al, 2021 ). For a more detailed description of the genetic data we refer to excellent recent reviews ( Kremer, 2019 ; Richardson and Petit, 2019 ).…”

TUB and ZNF532 Promote the Atoh1-Mediated Hair Cell Regeneration in Mouse Cochleae

“…A mutation of Tub causes loss of both tectorial membrane-attachment crowns (TM-ACs) and horizontal top connectors (HTCs), leading to severe hearing loss (Han et al, 2020 ). Sall1 mutation is responsible for Towners-Brocks syndrome (TBS) by displaying high-frequency sensorineural hearing loss in humans (Yang et al, 2021 ). Znf532 is a potential common target of Stat3 and Wnt/Pcp pathways (Savino et al, 2019 ).…”