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.

Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

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

No abstract

Simultaneous analysis of multiple genes using next‐generation sequencing (NGS) technology has become widely available. Copy‐number variations (CNVs) in disease‐associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H‐TAD)‐associated genes. Eight hundred ten patients suspected of H‐TAD were analyzed by targeted NGS analysis of 21 H‐TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi‐)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H‐TAD patients.

In spite of expansion of antenatal screening in the Netherlands in the 1990s and early 2000s, actual DS LB prevalence increased during this period. However, after 2002, this trend reversed, probably because of informing all pregnant women about prenatal testing since 2004 and the implementation of a national screening program in 2007.

In 31 symptomatic and 5 asymptomatic carriers of the amyloid precursor protein (APP) gene codon 693 mutation, 10 family members without mutation, and 5 carriers of the APP gene codon 692 mutation (3 with early-onset Alzheimer dementia, 2 with cerebral hemorrhage), a high frequency of the apolipoprotein E epsilon 4 allele was found. Age at onset, age at death, occurrence of dementia, and number of strokes did not differ between APP gene mutation carriers with or without epsilon 4 allele, showing that the clinical expression of these APP mutations is not influenced by the apolipoprotein E gene.

X-linked keratosis follicularis spinulosa decalvans (KFSD) is a rare disorder affecting the skin and eyes. The disease was previously mapped in an extended Dutch family to Xp2l.2-p22.2 between DXS16 and DXS269. Using five DNA probes and 14 CA repeat polymorphisms spanning this region an extensive linkage study was performed in the same pedigree. The highest lod scores were 12-07 for DXS365 (pRX-314) at 0=0, 1172 for DXS418 (P122) at 0=0-015, and 10-93 for DXS989 (AFM135xe7) at 0 = 0045. Analysis of recombination events locates the gene for KFSD between AFM291wf5 and DXS1226 (AFM316yf5). This is region Xp22.13-p22.2, an area covering approximately 1 Mb. These data confirm and greatly refine the regional localisation of KFSD and greatly improve reliability of carrier detection. (JMed Genet 1995;32:736- A total of five DNA markers and 14 CA repeat polymorphisms was tested in the family. Characteristics of these DNA polymorphisms are listed in physical order in table 1, by using data as assigned at the 5th chromosome X workshop'0 and by others."-6 SOUTHERN ANALYSIS DNA aliquots of 5 ig were digested with the restriction enzymes MspI, PvuII, and TaqI, according to the manufacturer's recommendations. The fragments were separated by 0 7% agarose gel electrophoresis and transferred to nylon filters (Hybond-N® Amersham) by means of alkaline blotting. Hybridisation with cx2P-dCTP labelled probes pD2 (DXS43), CRI-L1391 (DXS274), pQST1H3 (DXS257), and B24 (DXS67) was performed at 65°C overnight according to Church and Gilbert.'7 Filters were washed to a stringency of 1 x SSC/0-1% SDS, followed by autoradiography for one to three days using an intensifying screen. MICROSATELLITE MARKER ANALYSISAmplification of microsatellites (table 1) was performed in a Perkin Elmer Cetus thermal cycler. The reaction volume was 15 p1 containing 10 mmol/l MgClI, 10mmol/l Tris-HCI, pH 9-0; 50 mmol/l KCI; 0 01% gelatine; 0-1% Triton X-100; 0 6U Amplitaq® (Cetus Inc); 0 2mmol/l each of dATP, dGTP, and dTTP; 0-025 mmol/l dCTP; 0-27 pmol c32P-dCTP (at 3000 Ci/mmol); 5 pmol ofeach oligonucleotide primer, and 200 ng of genomic DNA template. An initial denaturation step of five minutes at 94°C was followed by 25 to 30 cycles of one minute at 94°C, two minutes at 736 on 10 May 2018 by guest. Protected by copyright.