Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome

Abstract

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

A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype

“…Three previously described patients with AUTS2 syndrome were re-evaluated and included: proband 5 (is proband 2 in reference 2), proband 6 (is proband 9 in reference 1) and proband 7 (is proband 1 in reference 2) 1 2. The age of the probands varied from 11 months to 59 years.…”

“…Clinical photographs of the face, body, hands and feet were taken and (where necessary) medical records reviewed with permission of the patients and/or their parents. Three previously described adult cases were re-evaluated by GB and were included because their clinical phenotype can now be described in more detail 1 2…”

“…AUTS2 syndrome (OMIM #615834), first described in 2013, is characterised by intellectual disability (ID) and microcephaly and is caused by defects of the AUTS2 gene 1 2…”

“…Forty-one had (intragenic) deletions of AUTS2 , mostly limited to AUTS2, but in a few including a maximum of two downstream genes (size 50 kb to 4.5 Mb). Furthermore, there were six translocations and two inversions with a breakpoint in AUTS2 , and finally, one ‘2 bp deletion’ has been described 1 2 10–22. There is evidence for a genotype–phenotype correlation.…”

“…This hampers clinical counselling of newly diagnosed patients with AUTS2 syndrome and their parents that have detailed questions about the developmental problems and health issues they might have to expect. Here, we describe a detailed and standardised (re)evaluation of 10 newly diagnosed and 3 formerly described patients with AUTS2 syndrome including 6 adults 1 2…”