Homozygous SALL1 mutation causes a novel multiple congenital anomaly-mental retardation syndrome.
OBJECTIVE
To delineate a novel autosomal recessive multiple congenital anomaly-mental retardation (MCA-MR) syndrome in 2 female siblings of a consanguineous pedigree and to identify the disease-causing mutation.


METHODS
Both siblings were clinically characterized and homozygosity mapping and sequencing of candidate genes were applied. The contribution of nonsense-mediated messenger RNA (mRNA) decay to the expression of mutant mRNA in fibroblasts of a healthy carrier and a control was studied by pyrosequencing.


RESULTS
We identified the first homozygous SALL1 mutation, c.3160C > T (p.R1054*), in 2 female siblings presenting with multiple congenital anomalies, central nervous system defects, cortical blindness, and absence of psychomotor development (ie, a novel recognizable, autosomal recessive MCA-MR). The mutant SALL1 transcript partially undergoes nonsense-mediated mRNA decay and is present at 43% of the normal transcript level in the fibroblasts of a healthy carrier.


CONCLUSIONS
Previously heterozygous SALL1 mutations and deletions have been associated with dominantly inherited anal-renal-radial-ear developmental anomalies. We identified an allelic recessive SALL1-related MCA-MR. Our findings imply that quantity and quality of SALL1 transcript are important for SALL1 function and determine phenotype, and mode of inheritance, of allelic SALL1-related disorders. This novel MCA-MR emphasizes SALL1 function as critical for normal central nervous system development and warrants a detailed neurologic investigation in all individuals with SALL1 mutations.
Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Austria. julia.vodopiutz@meduniwien.ac.at
Julia
J
Vodopiutz
Heinz
H
Zoller
Aimée L
AL
Fenwick
Richard
R
Arnhold
Max
M
Schmid
Daniela
D
Prayer
Thomas
T
Müller
Andreas
A
Repa
Arnold
A
Pollak
Christoph
C
Aufricht
Andrew O M
AO
Wilkie
Andreas R
AR
Janecke
D000015:Abnormalities, Multiple / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D017880:Limb Deformities, Congenital / Q000235:genetics*; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay; D010375:Pedigree; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
C104146:SALL1 protein, human; D014157:Transcription Factors