Undiagnosed Disease Network collaborative approach in diagnosing rare disease in a patient with a mosaic CACNA1D variant.

The Undiagnosed Disease Network (UDN) is comprised of clinical and research experts collaborating to diagnose rare disease. The UDN is funded by the National Institutes of Health and includes 12 different clinical sites (About Us, 2022). Here we highlight the success of collaborative efforts within the UDN Clinical Site at Vanderbilt University Medical Center (VUMC) in utilizing a cohort of experts in bioinformatics, structural biology, and genetics specialists in diagnosing rare disease. Our UDN team identified a de novo mosaic CACNA1D variant c.2299T>C in a 5-year-old female with a history of global developmental delay, dystonia, dyskinesis, and seizures. Using a collaborative multidisciplinary approach, our VUMC UDN team diagnosed the participant with Primary Aldosteronism, Seizures, and Neurologic abnormalities (PASNA) OMIM: 615474 due to a rare mosaic CACNA1D variant (O'Neill, 2013). Interestingly, this patient was mosaic, a phenotypic trait previously unreported in PASNA cases. This report highlights the importance of a multidisciplinary approach in diagnosing rare disease.

Novel variant in CADM3 causes Charcot-Marie-Tooth disease.

CADM3 has been recently reported causing a rare axonal Charcot-Marie-Tooth disease in three independent Caucasian families carrying a recurrent change. We describe the first alternative causative mutation in CADM3 in a family from black African and also observed de novo in a patient of Caucasian ancestry. The disease inheritance was consistent with autosomal dominant and sporadic patterns, respectively. Eight patients and their relatives were enroled from both families. The mean age at diagnosis was 33.9 years, and walking difficulty was commonly the first symptom. Neurological examination showed distal muscle weakness and atrophy, sensory loss and foot and hand deformities. A high clinical variability was noted, but as seen in CADM3-associated neuropathy, symptoms were more pronounced in the arms in some patients. Nerve conduction studies showed no response in most of the examined nerves, and an axonal type of neuropathy, where recorded. Whole exome sequencing revealed a novel missense variant (c.1102G>T; Gly368Cys) in CADM3, segregating with the disease. Functional analyses showed a significant decrease in CADM3-Gly368Cys protein levels in the membrane and major structural changes in its predicted secondary structure. Therefore, we extend the genotype spectrum of CADM3, underlining the need for genetic studies in underrepresented populations like in Africa.