Purpose This report describes the NIH Undiagnosed Diseases Program (UDP), details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate over its first two years. Methods Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density SNP arrays and whole exome or genome analysis. Results Of 1191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the NIH Clinical Center on the UDP service. Of those, 47% were children, 55% were females, and 53% had neurological disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathological, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based upon SNP array analysis and three others using WES and filtering of variants. Two new disorders were discovered. Analysis of the SNP-array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. Conclusions The NIH UDP addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies, and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.

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MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3′ region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma and other cancers, while germline variants have recently been identified in seven patients with a syndrome associating cardiac, facial and digital anomalies with developmental delay. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants through identification and description of 45 new patients, and to determine the effects of the variants at a molecular level through transcriptomic analysis of patient fibroblasts.Methods We performed exome, targeted capture and Sanger sequencing in a series of patients with undiagnosed developmental disorders. Phenotypic and mutational comparisons Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation We hope you will consider our manuscript for publication in Genetics in Medicine and we look forward to hearing your response.

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