Role of CAMK2D in neurodevelopment and associated conditions.

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review.

Contiguous ABCD1/ DXS1357E deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, ABCD1 and BCAP31 (formerly known as DXS1357E). Only nine individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss-of-function variants in BCAP31 cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH). Isolated pathogenic intragenic variants in ABCD1 are associated with the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood-onset neurodegeneration and high levels of very-long-chain fatty acids (VLCFA). While increased VLCFA levels also feature in CADDS, the few patients described to date all presented as neonates with a severe phenotype. Here we report a tenth individual with CADDS, a male infant with dysmorphic facial features who was diagnosed through ultra-rapid whole genome sequencing (WGS) in the setting of persistent cholestatic liver disease, sensorineural hearing loss, hypotonia and growth failure and developmental delay. Biochemical studies showed elevated VLCFA and mildly reduced plasmalogens. He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype. We also review the genetic, phenotypic, and biochemical features in previously reported individuals with CADDS.

Scaling national and international improvement in virtual gene panel curation via a collaborative approach to discordance resolution.

Clinical validity assessments of gene-disease associations underpin analysis and reporting in diagnostic genomics, and yet wide variability exists in practice, particularly in use of these assessments for virtual gene panel design and maintenance. Harmonization efforts are hampered by the lack of agreed terminology, agreed gene curation standards, and platforms that can be used to identify and resolve discrepancies at scale. We undertook a systematic comparison of the content of 80 virtual gene panels used in two healthcare systems by multiple diagnostic providers in the United Kingdom and Australia. The process was enabled by a shared curation platform, PanelApp, and resulted in the identification and review of 2,144 discordant gene ratings, demonstrating the utility of sharing structured gene-disease validity assessments and collaborative discordance resolution in establishing national and international consensus.

NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism.

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.

Detection of Right-to-Left Cardiac Shunt in the Absence of Transcranial Acoustic Bone.

PURPOSE: Paradoxical thrombotic embolism via right-to-left cardiac shunt (RLS) is a risk factor of cryptogenic ischemic stroke. Transtemporal Doppler (TTD) is a valid method used in the detection of patent foramen ovale (PFO). Temporal acoustic bone windows are missing with increasing age and in some younger subjects. We studied prospectively whether Doppler ultrasound of the cervical arteries (submandibular internal carotid artery [ICA] and vertebral artery [VA]) is an alternative, when compared to TTD, in the detection and quantification of PFO. MATERIAL AND METHODS: A total of 94 patients with sufficient temporal bone windows suffering from recent ischemic stroke underwent TTD and ICA (n = 51) or TTD and VA (n = 43). After injection of microbubbles, the numbers of artificial high-intensity signals (HITS) were recorded at rest and after Valsalva maneuver. RESULTS: For 47 patients in the ICA group, an RLS was found at rest in 23 patients and after Valsalva in 28 patients. At rest, sensitivity was 100%, specificity 96%, positive predictive value (ppv) 95.6%, and negative predictive value (npv) 100%. After Valsalva, sensitivity was 100%, specificity 95%, ppv 96.4%, npv 100%. For 43 patients in the VA group an RLS was found at rest in 14 patients and after Valsalva in 19 patients. At rest, sensitivity was 71.4%, specificity 100%, ppv 100%, and npv 87.8%. After Valsalva, 94.4%, 96%, 94.4%, and 96%, respectively. Pearson's correlations of the number of HITS between TTD and ICA and between TTD and VA were highly significant. CONCLUSIONS: When transcranial acoustic bone windows are missing, Doppler ultrasound of the cervical submandibular ICA and VAs are valid screening methods to detect RLS due to a PFO.

Reversed flow in the external carotid artery despite a patent but stenosed common carotid artery.

BACKGROUND AND PURPOSE: Occlusion of the common carotid artery (CCA) is generally associated with an occlusion of the ipsilateral internal carotid artery (ICA) or of the external carotid artery (ECA) or of both. Sometimes, collateral circulation to the ECA may preserve patency of the ICA via retrograde perfusion through the bulb. We herewith report a case of reversed flow in the ECA in the presence of a patent but stenosed CCA as diagnosed with color-coded duplex flow imaging (CDFI). CASE REPORT: This 85-year-old right-handed man was admitted for rapidly regressive acute dysarthria associated with left hemiparesis. Diffusion-weighted magnetic resonance (MR) imaging showed an acute ischemic lesion in the territory of the right middle cerebral artery. MR angiography showed patency of the right ICA and ECA but an occlusion of the CCA was suspected. CDFI demonstrated patency of the right CCA with a high-resistance pattern due to a large, partially calcified, stenosing atheromatous plaque. Surprisingly, reversed flow was observed in the right ECA of which signal was dampened. CONCLUSION: Collateralization with reversed flow in the ECA may occur in a patent but stenosed CCA associated with a high-grade stenosis of the carotid bifurcation. CDFI is a very useful tool to detect such hemodynamic conditions.

Retronasal olfactory function in Parkinson's disease.

OBJECTIVES/HYPOTHESIS: Orthonasal olfaction is severely altered in PD patients. Retronasal olfactory function has been shown to be preserved under certain conditions even in the absence of orthonasal function. This study was undertaken to investigate retronasal versus orthonasal olfactory function in Parkinson's disease (PD). STUDY DESIGN: Prospective study. METHODS: A total of 45 PD patients (mean age, 61 years; range 26-82 years) underwent orthonasal olfactory testing with a standardized olfactory test (Sniffin' Sticks) and retronasal olfactory testing with a 10-item identification kit based on aromatized powders. RESULTS: Regarding orthonasal tests, all PD patients scored within the range of hyposmia and functional anosmia. The mean correct orthonasal identification score for PD patients was 56% +/- 2.6%, and the mean retronasal identification rate was 60% +/- 3%. There was no significant difference between ortho- and retronasal odor identification (P = .15). CONCLUSIONS: The present study shows that retronasal and orthonasal olfactory function are severely impaired in PD patients, and this impairment is of similar magnitude for both functions. The contribution of this finding to the food-intake behavior of PD patients is discussed.

Transforaminal Doppler: an alternative to transtemporal approach for right-to-left cardiac shunt assessment.

BACKGROUND: Paradoxical thrombotic embolism via right-to-left shunt is a risk factor for ischemic stroke, especially in younger subjects. Transtemporal Doppler shows a sensibility and specificity in the detection of patent foramen ovale comparable to that of transesophageal echocardiography, but even younger patients may not have a sufficient acoustic temporal bone window (up to 10%). METHODS AND RESULTS: We thus studied prospectively in 74 patients subsequent to a recent stroke of undetermined origin whether transforaminal (foramen magnum) Doppler is an alternative to transtemporal Doppler in the detection and quantification of right-to-left cardiac shunt. We found a highly significant correlation between the two methods. CONCLUSIONS: We conclude that transforaminal Doppler may be a complement and alternative to transtemporal Doppler and thus improve its value as a screening method for right-to-left cardiac shunt due to patent foramen ovale.