ABSTRACT
Background: Congenital heart defects (CHD) and congenital anomalies of the kidney and urinary tract (CAKUT) account for significant morbidity and mortality in childhood. Dozens of monogenic causes of anomalies in each organ system have been identified. However, even though 30% of CHD patients also have a CAKUT and both organs arise from the lateral mesoderm, there is sparse overlap of the genes implicated in the congenital anomalies for these organ systems. We sought to determine whether patients with both CAKUT and CHD have a monogenic etiology, with the long-term goal of guiding future diagnostic work up and improving outcomes. Methods: Retrospective review of electronic medical records (EMR), identifying patients admitted to Rady Children's Hospital between January 2015 and July 2020 with both CAKUT and CHD who underwent either whole exome sequencing (WES) or whole genome sequencing (WGS). Data collected included demographics, presenting phenotype, genetic results, and mother's pregnancy history. WGS data was reanalyzed with a specific focus on the CAKUT and CHD phenotype. Genetic results were reviewed to identify causative, candidate, and novel genes for the CAKUT and CHD phenotype. Associated additional structural malformations were identified and categorized. Results: Thirty-two patients were identified. Eight patients had causative variants for the CAKUT/CHD phenotype, three patients had candidate variants, and three patients had potential novel variants. Five patients had variants in genes not associated with the CAKUT/CHD phenotype, and 13 patients had no variant identified. Of these, eight patients were identified as having possible alternative causes for their CHD/CAKUT phenotype. Eighty-eight percent of all CAKUT/CHD patients had at least one additional organ system with a structural malformation. Conclusions: Overall, our study demonstrated a high rate of monogenic etiologies in hospitalized patients with both CHD and CAKUT, with a diagnostic rate of 44%. Thus, physicians should have a high suspicion for genetic disease in this population. Together, these data provide valuable information on how to approach acutely ill patients with CAKUT and CHD, including guiding diagnostic work up for associated phenotypes, as well as novel insights into the genetics of CAKUT and CHD overlap syndromes in hospitalized children.
ABSTRACT
Merosin-deficient congenital muscular dystrophy 1A (MDC1A) is a devastating neuromuscular disease that results in children being confined to a wheelchair, requiring ventilator assistance to breathe and premature death. MDC1A is caused by mutations in the LAMA2 gene, which results in the partial or complete loss of laminin-211 and laminin-221, the major laminin isoforms found in the basal lamina of skeletal muscle. MDC1A patients exhibit reduced α7ß1 integrin; however, it is unclear how the secondary loss of α7ß1 integrin contributes to MDC1A disease progression. To investigate whether restoring α7 integrin expression can alleviate the myopathic phenotype observed in MDC1A, we produced transgenic mice that overexpressed the α7 integrin in the skeletal muscle of the dy(Wâ»/â») mouse model of MDC1A. Enhanced expression of the α7 integrin restored sarcolemmal localization of the α7ß1 integrin to laminin-α2-deficient myofibers, changed the composition of the muscle extracellular matrix, reduced muscle pathology, maintained muscle strength and function and improved the life expectancy of dy(Wâ»/â») mice. Taken together, these results indicate that enhanced expression of α7 integrin prevents muscle disease progression through augmentation and/or stabilization of the existing extracellular matrix in laminin-α2-deficient mice, and strategies that increase α7 integrin in muscle might provide an innovative approach for the treatment of MDC1A.
