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' 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.

Figure 1

(a) Proband 1 at the age of 24 years. (b) Proband 2 at the age of 20 years. These photographs show the slender build, the mild ptosis, small ears, deep nasal bridge, prominent nasal tip and broad nasal base, the thick lips and short philtrum in both men. The mild down-slanting palpebral fissures and the camptodactyly of the thumbs without other abnormalities of the hands were seen in proband 1, and shallow palmar creases of the PIP joints on digit V in proband 2. Parental consent was obtained.

Figure 2

(a) Schematic representation of the AUTS2 gene and the variants of probands 1 and 2. (b) Exome sequencing result of proband 1. The two-nucleotide deletion at the genomic position g.70227971 is shown in purple. The blue and green lines indicate the reads of the parents (only part of the reads are shown in this overview). The Sanger sequence result of the forward strand shows the frameshift (upper) and is compared with the normal Sanger sequence (lower). (c) The array results of proband 2 show the deletion of exon 6 (NG_034133.1) as indicated by the log R ratio of −0,5 and the absence of heterozygosity.