Currently, we reanalyze families with more than one plausible mutation, e.g. by studying knock-down fly models for the relevant gene defects (see below), as well as families where no single homozygous mutation has been found. In some of these families, the ID may be due to compound heterozygosity, i.e., it may be unrelated to the parental consanguinity, or the causative mutations may hide in introns or other non-coding sequences that have not been investigated so far. To unveil these missing mutations, whole genome sequencing has been performed in

11 of these families, and analysis of the results is ongoing.

In parallel, we have embarked on a second, even larger study encompassing almost 150 consanguineous families from Iran and Germany, including all remaining large families collected by our Iranian partner in the course of this long-standing collaboration. In most of these families, SNP typing revealed multiple homozygous linkage intervals, which renders targeted exon enrichment with custom-made arrays costly and tedious. Therefore, and in order to detect compound heterozygosity, we have turned to whole exome sequencing instead, Currently, we reanalyze families with more than one plausible mutation, e.g. by studying knock-down fly models for the relevant gene defects (see below), as well as families where no single homozygous mutation has been found. In some of these families, the ID may be due to compound heterozygosity, i.e., it may be unrelated to the parental consanguinity, or the causative mutations may hide in introns or other non-coding sequences that have not been investigated so far. To unveil these missing mutations, whole genome sequencing has been performed in

11 of these families, and analysis of the results is ongoing.

In parallel, we have embarked on a second, even larger study encompassing almost 150 consanguineous families from Iran and Germany, including all remaining large families collected by our Iranian partner in the course of this long-standing collaboration. In most of these families, SNP typing revealed multiple homozygous linkage intervals, which renders targeted exon enrichment with custom-made arrays costly and tedious. Therefore, and in order to detect compound heterozygosity, we have turned to whole exome sequencing instead,

(Thomas Wienker, Wei Chen, Hao Hu; Thomasz Zemojtel, Dept. Computational Molecular Biology)

High-throughput sequencing techniques have not only revolutionized the elucidation of single gene disorders, but also provided the basis for comprehensive diagnostic tests to rule out mutations in all known disease genes. In collaboration with Stephen Kingsmore (Children’s Mercy Hospital, Kansas City, USA), the Pediatric Department of the Berlin University Hospital Charité and Wei Chen at the MDC Berlin, we have developed a clinical entry test for children with severe ID and/or unexplained developmental delay. This test, baptized ‘MPIMG1’, encompasses numerous severe childhood disorders, all published ID genes as well as the many novel ones identified by our group. In principle, this test can also be employed for non-invasive preconception carrier detection to rule out elevated parental risks for children with severe recessive disorders. This application renders it particularly useful for consanguineous parents and for countries from the so-called ‘Consanguinity Belt’ that extends from the Maghreb to India.

Until our department will be officially closed in late fall 2014 and the EU-FP7 project will expire in April 2015, most of our remaining resources will be used to successfully conclude three ongoing, closely related projects.

First, the long-standing collaboration with our Iranian partner will reach its natural end when all ARID families collected since 2004 have been analyzed and funding of both groups by the afore-mentioned EU project will be discontinued. We expect that until then, our research into autosomal and X-linked forms of ID will remain internationally competitive.

Secondly, provided that residual administrative hurdles can be overcome, we will implement our novel MPIMG1 test at the Charité – Universitätsmedizin Berlin, the Children’s Mercy Hospital in Kansas City and elsewhere as a first-line diagnostic tool for all known genetic defects that cannot be readily diagnosed by clinical examination alone. Thereafter, we intend to offer this diagnostic and carrier test to improve genetic health care in selected countries with frequent parental consanguinity, intellectual disability and developmental delay.

Finally, in collaboration with a Dutch group, we are about to shed light on the old question whether ID genes also have a role as determinants of the normal IQ distribution, as postulated by Lehrke9  40 years ago. Targeted exon enrichment and next generation sequencing in ~ 170 selected ID genes will be performed to test the hypothesis that there is an inverse relationship between the IQ of the proband and the number of subtle mutations in these genes. While the analysis of these data may turn out to be quite difficult and time-consuming, we expect that this investigation will be completed well within the available time-frame, even if it should turn out that follow-up studies will be required to answer this question in full.