Autosomal Recessive Infantile Hyaline Fibromatosis Identified Using Artificial Intelligence-Assisted Rapid Whole Genome Sequencing: A Rare, Multisystemic, Hereditary Disorder.

Infantile hyaline fibromatosis syndrome (HFS) is an ultra-rare genetic condition characterized by the deposition of hyaline material in the skin, muscle, and viscera. Potential complications include debilitating joint contractures, coarse facial features, recurrent infections, failure to thrive, and death. Here, we present the case of a six-month-old infant with a history of painful extremity contractures, global developmental delay, neck hemangioma, and feeding intolerance presenting to our institution with abdominal distension. The multi-systemic, rapidly progressing, severe nature of her symptoms prompted consultation with inpatient pediatric genetics. Per their recommendation, rapid whole-genome sequencing (rWGS) was done with Fabric GEM®-assisted artificial intelligence (Fabric Genomics, Oakland, California, United States) at Rady Children's Hospital Institute for Genomic Medicine (San Diego, California, United States), revealing homozygous pathogenic variant c.652T>C; P.Cys218Arg in the ANTXR2 gene consistent with HFS. This case was significant not only for its rarity, but also its early manifestation of symptoms, wide range of affected body systems, and severity of symptoms, which together present a fascinating diagnostic dilemma for future clinicians that should be taken into consideration. It also highlights the increasing utility of AI-assisted rWGS as a diagnostic tool for medically complex patients with unknown multisystemic hereditary conditions.

Flow interruption compared to forced oscillatory maneuvers and esophageal balloon/pneumotachography for measurement of respiratory resistance in the horse.

Pulmonary function testing is critical to the diagnosis of equine asthma (EA), an important cause of respiratory disease in the horse, but its clinical use has remained elusive, unfortunately, due to the complexity of reference methods, esophageal balloon/pneumotachography (EBP), and forced oscillatory mechanics (FOM), so we sought a noninvasive, portable method for use in horses through rapid interruption of airflow for equilibration of alveolar pressure with proximal airway pressure, termed flow interruption (FI). Resistance (RINT) was computed as the relationship between the change in pressure at the nose before and immediately after interruption and flow immediately before interruption. A pilot study in five healthy university-owned animals using EBP and FI showed good correspondence between the two methods: RINT (0.33 ± 0.05 cmH2O/L/s) and RL (0.31 ± 0.06 cmH2O/L/s). In two separate populations of client-owned horses, with random assignment of methods to FI versus EBP (n = 8), RINT showed good correlation with RL in horses (rs = 0.995, P = 0.0002) and accords with RL, with no significant difference between RINT and RL. Using FOM (n = 12), RINT (0.67 ± 0.31 cmH2O/L/s) has good correlation with RRS measured with FOM (r = 0.834, P = 0.0001), but is consistently smaller than RRS (0.74 ± 0.33 cmH2O/L/s). Histamine bronchoprovocation (HBP) was performed in a subset of these horses: FI classified one horse in six as less reactive than did EBP, and FI classified one horse in seven as less reactive than did FOM.NEW & NOTEWORTHY We developed and document for the first time the use of flow interruption for the rapid and noninvasive measurement of resistance in equine patients and demonstrated short- and long-term stability and accuracy in comparison with the reference methods.

Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects.

Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in NKX2.5, GATA4, TBX5, and CHD7. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0-kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37/hg19]) that included exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD.