Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.
The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.
The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.
AUTS2 syndrome is characterized by low birth weight, feeding difficulties, intellectual disability, microcephaly and mild dysmorphic features. All affected individuals thus far were caused by chromosomal rearrangements, variants at the base pair level disrupting AUTS2 have not yet been described. Here we present the full clinical description of two affected men with intragenic AUTS2 variants (one two-base pair deletion in exon 7 and one deletion of exon 6). Both variants are de novo and are predicted to cause a frameshift of the full-length transcript but are unlikely to affect the shorter 3 0 transcript starting in exon 9. The similarities between the phenotypes of both men are striking and further support that AUTS2 syndrome is a single gene disorder. ( European Journal of Human Genetics INTRODUCTIONDisruption of AUTS2 by translocations, inversions or deletions causes a syndromic form of intellectual disability. 1 Forty-four pathogenic disruptions of AUTS2 have been described: 6 translocations and 2 inversions with one breakpoint in AUTS2 and 36 deletions (with a size of 50 kb to 4.5 Mb) containing at least one exon and a maximum of two downstream genes. In most cases parental DNA was available.De novo occurrence could be confirmed in the majority of the patients, but in five families the deletions were inherited from an affected parent (twice), an unaffected father (once) or a parent of whom no clinical data were available (twice). 1-11 A detailed study of 17 affected individuals with a disruption of AUTS2 revealed a distinct AUTS2 syndrome characterized by intellectual disability, microcephaly, mild short stature, feeding problems, hypertonia or hypotonia and facial features, including ptosis, highly arched eyebrows, narrow mouth and micro/retrognathia. 1 The AUTS2 syndrome severity score, expressed as the sum of all features seen more than once in unrelated affected individuals, is a measure of the severity and specificity of the phenotype. The median AUTS2 syndrome severity score of individuals with a genomic rearrangement/ deletion involving the 3 0 region of AUTS2 was significantly higher than that of individuals with 5 0 deletions. The 3 0 end of the gene harbors an alternative transcript that is (like the full-length transcript) expressed in human brain and starts in exon 9. The short transcript is able to rescue the phenotype of AUTS2 zebrafish morphants. These two observations indicate that the 3 0 region of AUTS2 contains important functional domains. 1 Here we report a deletion of two nucleotides, the first pathogenic variant at the base pair level, in a young adult with a syndromic form
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