title: Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region.
abstract: Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.
authors.affiliation: Institut für Humangenetik und Anthropologie, Universität Freiburg, Freiburg, Germany.
authors.forename: Elke M
authors.initials: EM
authors.lastname: Botzenhart
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bartalini
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.forename: Frances
authors.initials: F
authors.lastname: Elmslie
authors.forename: Karen L
authors.initials: KL
authors.lastname: Chong
authors.forename: Katie
authors.initials: K
authors.lastname: Christy
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Torres-Martinez
authors.forename: Cesare
authors.initials: C
authors.lastname: Danesino
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Sixto
authors.initials: S
authors.lastname: Garcia-Minaur
authors.forename: Yorck
authors.initials: Y
authors.lastname: Hellenbroich
authors.forename: Beverly N
authors.initials: BN
authors.lastname: Hay
authors.forename: Maila
authors.initials: M
authors.lastname: Penttinen
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
authors.forename: Paulien
authors.initials: P
authors.lastname: Terhal
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Margo L
authors.initials: ML
authors.lastname: Whiteford
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C104146:SALL1 protein, human; D014157:Transcription Factors