Implications for genotype-phenotype predictions in Townes-Brocks syndrome: Case report of a novel SALL1 deletion and review of the literature

The Heart Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 03/2012; 158A(3):533-40. DOI: 10.1002/ajmg.a.34426
Source: PubMed


Townes-Brocks syndrome (TBS) is a well-described genetic syndrome characterized by anal, ear, and thumb anomalies and variable expressivity. Over 60 nonsense and frameshift mutations have been identified in SALL1, the zinc finger transcription factor causing TBS, and are proposed to cause disease via a dominant negative mechanism. In contrast, only four deletions have been described, with mild phenotypes reported as a result of haploinsufficiency. We report on a family with features of TBS in whom a novel 149 kb deletion spanning the SALL1 gene was identified by high resolution cytogenetics SNP microarray. We review the available genotype-phenotype information for all known truncating mutations and deletions. Taken together, they do not support the correlation of SALL1 deletions with a milder TBS phenotype and highlight a need for more robust clinical phenotyping combined with investigation of mutational mechanism.

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    • "Moreover, the rarity of the condition is paralleled by the lack of unequivocal data to support the previous genotype-phenotype correlations . For example, developmental delay, already mentioned as an occasional feature of the syndrome, is mostly accounted for by genomic deletions encompassing SALL1 and involving also other genes in 16q12.1 [158]. Finally, the homozygous c.3160C>T, p.R1054* SALL1 mutation in 2 female siblings has been associated with a severe phenotype featured by multiple congenital anomalies, central nervous system defects, cortical blindness, and profound developmental delay [165]. "
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    ABSTRACT: Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the con genital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.
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    • "In humans, the SALL1 gene is located on 16q12.1 and encodes zinc finger domain proteins and alanine and glutamine heavy domains, all of which are associated with transcription factors. The prevalence of TBS in the general population has been estimated at 1 in 250,000 [Martinez-Frias et al., 1999], but is probably much higher due to common shared characteristics with VATER association and subtle variable phenotypes in many TBS patients [Miller et al., 2011]. The hallmark clinical features of TBS are the classic triad of anal, ear, and thumb anomalies [Kohlhase, 2007] which are inherited in an autosomal dominant manner [Townes and Brocks, 1972]. "
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    ABSTRACT: Townes-Brocks syndrome is a recognizable variable pattern of malformation caused by mutations to the SALL1 gene located on chromosome 16q12.1. Only three known cases of Townes-Brocks syndrome with proven SALL1 gene mutation and concurrent endocrine abnormalities have been previously documented to our knowledge [Kohlhase et al., 1999; Botzenhart et al., 2005; Choi et al., 2010]. We report on two unrelated patients with Townes-Brocks syndrome who share an identical SALL1 mutation (c.3414_3415delAT), who also have endocrine abnormalities. Patient 1 appears to be the first known case of growth hormone deficiency, and Patient 2 extends the number of documented mutation cases with hypothyroidism to four. We suspect endocrine abnormalities, particularly treatable deficiencies, may be an underappreciated component to Townes-Brocks syndrome. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Sep 2013 · American Journal of Medical Genetics Part A

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