Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant.

Inherited syndromes of congenital enteropathy are rare, with many genetic causes described. Mutations of the AP1S1 gene results in the syndrome of intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (IDEDNIK, formerly in the medical literature as MEDNIK). The clinicopathologic features of the enteropathy in IDEDNIK syndrome have not been fully explored. We describe a female infant who presented with metabolic acidosis, lethargy, and 14 watery stools per day. In the intensive care unit she required parenteral nutrition. She was found to have a novel homozygous pathogenic variant in the AP1S1 gene c.186T>G (p.Y62*). Esophagogastroduodenoscopy and colonoscopy at 6 months of age were grossly normal. However, histologic sections of the duodenum showed mild villous blunting and enterocytes with cytoplasmic vacuoles. CD10 immunostaining highlighted the disrupted brush border. MOC31 immunostaining was wild-type with a membranous pattern of expression. Electron microscopy of the duodenum showed scattered enterocytes cells with shortened and disrupted apical microvilli. Although there is a mixed gap diarrhea and disrupted brush border, there are no significant inclusions typical of microvillus inclusion disease, nor tufted enterocytes typical of tufting enteropathy, making the clinical and histopathologic features for this syndrome unique.

A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder.

Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.

Neonatal lupus is a novel cause of positive newborn screening for X-linked adrenoleukodystrophy.

We report three unrelated individuals, each exposed to maternal autoantibodies during gestation and found to have elevated very long-chain fatty acids (VLCFAs) in the newborn period after screening positive by California newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD). Two probands presented with clinical and laboratory features of neonatal lupus erythematosus (NLE); the third had features suggestive of NLE and a known maternal history of Sjogren's syndrome and rheumatoid arthritis. In all three individuals, subsequent biochemical and molecular evaluation for primary and secondary peroxisomal disorders was nondiagnostic with normalization of VLCFAs by 15 months of age. These cases add to the expanding differential diagnosis to consider in newborns who screen positive for ALD via elevated C26:0-lysophosphatidylcholine. Though the pathophysiology of how transplacental maternal anti-Ro antibodies damage fetal tissue is not well-understood, we postulate that the VLCFA elevations reflect a systemic inflammatory response and secondary peroxisomal dysfunction that improves once maternal autoantibodies wane after birth. Additional evaluation of this phenomenon is warranted to better understand the intricate biochemical, clinical, and possible therapeutic overlap between autoimmunity, inflammation, peroxisomal dysfunction, and human disease.

Phenotypic variability in RERE-related disorders and the first report of an inherited variant.

RERE-related disorders, also known as Neurodevelopmental Disorders with or without Anomalies of the Brain, Eye, or Heart (NEDBEH), are caused by heterozygous pathogenic variants in the arginine-glutamic acid dipeptide repeats gene (RERE). Up-to-date, 20 cases have been reported with the core characteristics of developmental delay, intellectual disability, and/or autism spectrum disorder. Here, we describe three additional cases. In the first case, the patient was found to have a previously reported de novo missense variant; her clinical findings of global developmental delay, intellectual disability, autism spectrum disorder, vision abnormalities, musculoskeletal anomalies, dysmorphic facial features, and a congenital heart defect strengthen existing genotype-phenotype correlations. We also describe the first inherited variant in RERE, found in a patient (case 2) with developmental delay, autism, and hyperopia and his mother (case 3) with ADHD, myopia, and history of mild speech delay. Lastly, by summarizing the clinical features presented in the 23 cases now reported, we provide an updated review of the literature.

A survey of program directors for combined pediatrics and medical genetics and genomics residency programs: Perspectives when evaluating applicants.

While combined pediatrics and medical genetics and genomics residency programs are growing in number and applicants, there are still workforce shortages within the medical genetics field. Medical students would benefit from additional information on the training pathways and insight into the application process itself. Program Directors of combined pediatrics and medical genetics and genomics residency programs were surveyed to characterize factors that influence interview selection and rank list decisions, application logistics, recruitment, and training pathways. When evaluating applicants, representatives from both pediatrics and medical genetics are involved in the screening process. Additionally, both groups value prior research experience, but do not have a clear preference for a particular subcategory or domain of research. Most program directors think that all currently-available training pathways can provide optimal training. Further action is needed to provide medical students with the knowledge to make more informed decisions about their career and medical school advisors with objective data to counsel students. There was support among program directors to initiate consideration of creating a pathway for medical students to match directly into a medical genetics and genomics residency.

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

PURPOSE: Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research. METHODS: We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability. RESULTS: We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders. CONCLUSION: The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268.