Advancing Clinical Practice through Integration of Congenital Cytomegalovirus (cCMV) Testing with Newborn Hearing Screening at Mayo Clinic

Although cCMV is the leading non-genetic cause of childhood hearing loss in the United States, neither targeted nor universal screening protocols have been well established to identify cCMV in newborns. Moreover, until cCMV testing is universal, clinical protocols need to account for the complexities of individualized care in partnership with interprofessional care teams. This work addressed an immediate clinical practice need to identify cCMV with subsequent hearing monitoring of babies who test positive for cCMV. This effort focused on three primary objectives to: 1) define interprofessional, team-based approach to facilitate care pathways; 2) develop a clinical workflow for all babies who refer on inpatient hearing screening to be tested for cCMV by 21 days of age; 3) develop a hearing monitoring plan for all babies who test positive for cCMV. The development and integration of our interprofessional, team-based approach to institute cCMV testing by 21 days of age on all babies who refer inpatient newborn hearing screening and subsequent monitoring is described. Our observed referral rate was lower than predicted (2.7%) from existing literature with only one positive cCMV outcome noted in the two-year span. This study demonstrates the feasibility of a hearing-targeted cCMV testing paradigm in our clinic practice

Familial recurrence of SOX2 anophthalmia syndrome:phenotypically normal mother with two affected daughters

The SOX2 anophthalmia syndrome is emerging as a clinically recognizable disorder that has been identified in 10–15% of individuals with bilateral anophthalmia. Extra-ocular anomalies are common. The majority of SOX2 mutations identified appear to arise de novo in probands ascertained through the presence of anophthalmia or microphthalmia. In this report, we describe two sisters with bilateral anophthalmia/microphthalmia, brain anomalies and a novel heterozygous SOX2 gene single-base pair nucleotide deletion, c.551delC, which predicts p.Pro184ArgfsX19. The hypothetical protein product is predicted to lead to haploinsufficient SOX2 function. Mosaicism for this mutation in the SOX2 gene was also identified in their clinically unaffected mother in peripheral blood DNA. Thus it cannot be assumed that all SOX2 mutations in individuals with anophthalmia /microphthalmia are de novo. Testing of parents is indicated when a SOX2 mutation is identified in a proband

Development and Notch Signaling Requirements of the Zebrafish Choroid Plexus

The choroid plexus (CP) is an epithelial and vascular structure in the ventricular system of the brain that is a critical part of the blood-brain barrier. The CP has two primary functions, 1) to produce and regulate components of the cerebral spinal fluid, and 2) to inhibit entry into the brain of exogenous substances. Despite its importance in neurobiology, little is known about how this structure forms.Here we show that the transposon-mediated enhancer trap zebrafish line Et(Mn16) expresses green fluorescent protein within a population of cells that migrate toward the midline and coalesce to form the definitive CP. We further demonstrate the development of the integral vascular network of the definitive CP. Utilizing pharmacologic pan-notch inhibition and specific morpholino-mediated knockdown, we demonstrate a requirement for Notch signaling in choroid plexus development. We identify three Notch signaling pathway members as mediating this effect, notch1b, deltaA, and deltaD.This work is the first to identify the zebrafish choroid plexus and to characterize its epithelial and vasculature integration. This study, in the context of other comparative anatomical studies, strongly indicates a conserved mechanism for development of the CP. Finally, we characterize a requirement for Notch signaling in the developing CP. This establishes the zebrafish CP as an important new system for the determination of key signaling pathways in the formation of this essential component of the vertebrate brain

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5

Background and Objectives KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.Methods We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.Results We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.Discussion We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.</p

Axenfeld-Rieger syndrome: new perspectives

Axenfeld-Rieger syndrome is a genetic disease affecting multiple organ systems. In the eye, this condition manifests with varying degrees of anterior segment dysgenesis and carries a high risk of glaucoma. Other associated systemic issues include cardiovascular outflow tract malformations, craniofacial abnormalities and pituitary abnormalities, which can result in severe endocrinological sequelae. Recent advances in molecular genetics have identified two major genes, PITX2 and FOXC1, demonstrating a wide spectrum of mutations, which aids in the molecular diagnosis of the disease, although evidence exists to implicate other loci in this condition. The management of individuals affected by Axenfeld-Rieger syndrome requires a multidisciplinary approach and would include dedicated surveillance and management of glaucoma, sensorineural hearing loss, and cardiac, endocrinological, craniofacial and orthopaedic abnormalities

Profound intellectual disability caused by homozygous TRAPPC9 pathogenic variant in a man from Malta

Abstract Background Intellectual disability is a complex multi‐faceted condition with diverse underlying etiologies. One rare form of intellectual disability is secondary to the loss of TRAPPC9, an activator of NF‐κB and a mediator of intracellular protein processing and trafficking. TRAPPC9 deficiency has been described in 48 patients with more than 15 pathologic variants. Method Clinical evaluation, magnetic resonance imaging, and whole‐exome sequencing were used to characterize the underlying cause of absent speech, restricted/repetitive behaviors, and worsening behavioral outbursts in 27‐year‐old man from Malta. Results Magnetic Resonance Imaging showed morphologic abnormalities, including global cerebral and cerebellar hypoplasia. Genetic analysis through Whole Exome Sequencing identified a homozygous deletion (c.568_574del) in TRAPPC9 resulting in a frameshift, premature stop codon, and ultimately a truncated protein (p.Trp190Argfs*95). In this case, the pathogenic variant was homozygous, identified in both of the parents without known consanguinity. Conclusion Given the phenotype and genotype consistent with a deficiency in TRAPPC9, it is likely that this patient represents a novel case of this rare genetic syndrome. Specifically, this case, in the context of 48 total reported patients, raises questions as to the geographic origin of the pathologic variant and optimal detection and therapeutic intervention for this condition

Alström syndrome caused by maternal uniparental disomy

Purpose: To describe a case of Alström syndrome arising from maternal uniparental disomy. Observations: A 13-month-old boy with poor vision and nystagmus was diagnosed with Alström syndrome based on genetic testing that identified a homozygous pathogenic variant, ALMS1 c.2141_2141del (p.Ser714Tyrfs*6), that was only found in his mother and not his father. In contrast to the usual autosomal recessive inheritance pattern in which a child inherits a variant from each parent, multi-step genetic testing of the child and both parents confirmed uniparental disomy as the mechanism of inheritance. Conclusions and Importance: Confirmation of uniparental disomy in autosomal recessive disorders allows for parental assurance that future offspring will be unaffected