Undiagnosed Diseases Program

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

FY23 was the first year in which the NIH Undiagnosed Diseases Program operated under funding from the school tax, i.e., the same group of NIH Institutes and Centers that support the NIH Clinical Center based upon the size of their intramural research budgets. For the previous 10 years (2013-2022), the UDP was funded by the Common Fund. William Gahl, MD, PhD, and Adams, MD, PhD, co-direct the UDP; Cynthia Tifft, MD, PhD, runs the Pediatric UDP; May Malicdan, MD, PhD, manages the UDPs translational research program; and Camilo Toro, MD, is the master neurologist who directs the adult portion of the UDP. In the first 8 months of FY23, the UDP reviewed 183 applications and evaluated 59 patients accounting for 135 adjusted patient days in the Clinical Center. This pace continued during the last third of the year. In FY23, children comprised 40% of the patients; 26 diagnoses were made. These included a 14 year-old girl from Nigeria with rickets and fractures due to a de novo pathogenic variant in SLC4A1, a13 year-old boy with gliomatosis cerebri, a 6 year-old boy with poor development, hypotonia, and dysmorphisms due to EIF3F variants, a 42 year-old man with seizures, acidosis, and impaired hearing due to 77% heteroplasmy in muscle tRNA-His, a 54 year-old male with autosomal dominant progressive myopathy due to a splicing variant in MYH2, a 23 year-old male with spinocerebellar ataxia and delays due to biallelic variants in PRDX3, a 5 year-old girl and her sib with hypotonia, language delay, and stereotypic movements due to MEF2C mutations, a 64 year-old woman with adult polyglucosan body disease due to GBE1 mutations, a 14 year-old girl with rickets due to SLC4A1 mutations, a 28 year-old male with cerebral cavernous malformations due to a KRIT1 mutation, a 39 year-old woman with atypical mycobacterium and cranial nerve involvement, a 31 year-old male with unstable gait and peripheral neuropathy due to biallelic SETX mutations, a 47 year-old with moving toes syndrome, 27 and 18 year-old males with delays and parkinsonism due to WARS2 mutations, an 11 year-old girl with dysmorphisms, growth delay, intellectual disability, and liver failure due to biallelic variants in NBAS, 7 and 8 year-old girls with poor development, renal failure, and trifunctional protein deficiency due to HADHB mutations, a 56 year-old female with quadriceps-sparing myopathy due to GNE mutations, a 13 year-old girl from Albania with delays, stroke, apraxia, seizures, and brain dysmorphisms due to a CACNA1A mutation, a 38 year-old man with cerebellar ataxia due to a de novo RAB3A mutation, and a 3 year-old boy with encephalopathy and low selenium due to PSTK mutations. In the past year, the UDP was involved in the discovery of several new disease mechanisms, including an autoinflammatory disease, pansclerotic morphea, due to a gain-of-function STAT4 variant driving IL-6 inflammation and treatable with JAK-STAT inhibition. UDP bench researchers also described decreased ATG4D cysteine protease activity responsible for impaired autophagic degradation of damaged neuronal organelles in an 11 year-old boy with speech and motor impairment due to biallelic ATG4D mutations. A 20 year old female UDP patient manifested neuroregression and progressive spasticity with biallelic pathogenic SNAPC4 variants; UDP bench investigators determined that these mutations reduced the function of snRNA Activating Protein Complex 4, causing reduced snRNA gene transcription required for splicing function. UDP scientists and clinicians also contributed to the elucidation of decreased actin skeleton organization due to a de novo variant in the transcription factor gene, MRTFB, in an 18 year-old woman with developmental delays and apraxia. Finally, the UDP team expanded the phenotype of TUBB4B tubulopathy by describing renal Fanconi syndrome in a 2 year-old girl with a previously undescribed mutation in TUBB4B. The mutation affects the GTP binding site of TUB4B, impairs tubulin disassembly, and likely prevents movement of phosphate transporters to the apical surface of renal tubular cells for phosphate reabsorption. In FY 23, the UDP led or contributed to 23 publications, including one each in the New England Journal of Medicine, American Journal of Human Genetics, Brain, Science Advances, Human Molecular Genetics, and two in Genetics in Medicine. Dr. Toro described the molecular basis of ROSAH syndrome (gain-of-function ALPK1 variants), helped publish a broad characterization of African Nodding Syndrome, reported a de novo HK1 (hexokinase 1) variant as a cause of Boucher-Neuhauser syndrome, described a myopathy due to a splice variant in MYH2, contributed to an article on pituitary hypersecretion due to-loss of-function PAM variants, described the use of TNF blockers to prevent stroke in patients with Adenosine Deaminase 2 Deficiency, and summarized the genetic bases of UDP patients with intracerebral calcifications. Other Section members reported the mechanism of haploinsufficiency of KMT5B in impairing murine and human neurodevelopment, provided insights gleaned from the UDP, contributed to an elucidation of disorders of mitochondrial and nuclear genome stability related to TOP3A variants, and contributed to the elucidation of neuroimaging and skeletal features of KBG syndrome. UDP investigators collaborated on patient-related UDP projects with physicians and scientists from NCI, NICHD, NHLBI, NINDS, NIAID, NIDDK, NIMH, NIDCR, NEI, and NHGRI. Members of the UDP searched the UDP database, UDPICS, for variants in genes of interest for a dozen intramural investigators. The Program trained 8 postbacc IRTAs and two graduate students in FY23; 4 current trainees are first authors of published articles. Dr. Adams conducted a Bioinformatic Journal Club and delivered lectures at the Genome School and at other national and international forums. Dr. Gahl conducts weekly UDP patient rounds, attended by 70-80 aspiring physicians and scientists. For the international rare disease community, Gahl leads the Undiagnosed Diseases Network International (UDNI), a consortium of 161 physicians and scientists from 49 nations. In FY23, Gahl coordinated the 11th UDNI conference in Vienna, established a Champions Initiative to foster UDPs in developing nations, and published papers on the value of clinical networks for rare diseases and the unmet needs of undiagnosed patients in various countries. With colleagues, he wrote articles on the UDN, insights gleaned from the UDP, and the relationship between the UDNI and a new journal entitled Rare. Gahl also delivered 7 invited national and international talks that featured the UDP, including the Roscoe Brady Award lecture for WORLDSymposium.