Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot ...deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy.
USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by ...hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.
AIM:To evaluate the risk associated with variants of the UNC5C gene recently suspected to predispose to familial colorectal cancer(CRC).METHODS:We screened patients with familial CRC forms as well as ...patients with sporadic CRCs.In a first time,we analyzed exon 11 of the UNC5C gene in 120unrelated patients with suspected hereditary CRC,58patients with suspected Lynch-associated cancer or polyposis,and 132 index cases of Lynch syndrome families with a characterized mutation in a DNA mismatch repair(MMR).Next,1023 patients with sporadic CRC and1121 healthy individuals were screened for the variants identified in patients with familial cancer.RESULTS:Of 120 patients with familial CRC of unknown etiology,one carried the previously reported mis-sense mutation p.Arg603Cys(R603C)and another exhibited the unreported variant of unknown significance p.Thr617Ile(T617I).The p.Ala628Lys(A628K)mutation previously described as the main UNC5C risk variant for familial CRC was not detected in any cases of familial CRC of unknown etiology,but was present in a patient with familial gastric cancer and in two Lynch syndrome patients in co-occurrence with MMR mutations.A statistically non-significant increase in cancer risk was identified in familial CRC and/or other Lynchassociated cancers(1/178 patients vs 2/1121 healthy controls,OR=3.2,95%CI:0.29-35.05,P=0.348)and in sporadic CRCs(4/1023 patients vs 2/1121 healthy controls,OR=2.2,95%CI:0.40-12.02,P=0.364).CONCLUSION:We confirm that UNC5C mutations are very rare in familial and sporadic CRCs,but further investigations are needed to justify routine UNC5C testing for diagnostic purposes.
We have characterized the human gene SLC39A4, which encodes a protein with features characteristic of a ZIP zinc transporter. The chromosomal location and expression of SLC39A4, together with ...mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition.
Zinc is essential to a wide range of cellular processes; therefore, it is important to elucidate the molecular mechanisms of zinc homeostasis. To date, no zinc transporters expressed at the ...enterocyte apical membrane, and so essential to mammalian zinc homeostasis, have been discovered. We identified hZTL1 as a human expressed sequence tag with homology to the basolateral enterocyte zinc transporter ZnT1 and deduced the full-length cDNA sequence by PCR. The protein of 523 amino acids belongs to the cation diffusion facilitator family of membrane transporters. Unusually, the predicted topology comprises 12 rather than 6 transmembrane domains. ZTL1 mRNA was detected by reverse transcription-PCR in a range of mouse tissues. A Myc-tagged hZTL1 clone was expressed in transiently transfected polarized human intestinal Caco-2 cells at the apical membrane. Expression of hZTL1 mRNA in Caco-2 cells increased with zinc supplementation of the nutrient medium; however, in the placental cell line JAR hZTL1 appeared not to be regulated by zinc. Heterologous expression of hZTL1 in Xenopus laevis oocytes increased zinc uptake across the plasma membrane. The localization, regulatory properties, and function of hZTL1 indicate a role in regulating the absorption of dietary zinc across the apical enterocyte membrane.
While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to ...understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.
Many monogenic disorders cause a characteristic facial morphology. Artificial intelligence can support physicians in recognizing these patterns by associating facial phenotypes with the underlying ...syndrome through training on thousands of patient photographs. However, this 'supervised' approach means that diagnoses are only possible if the disorder was part of the training set. To improve recognition of ultra-rare disorders, we developed GestaltMatcher, an encoder for portraits that is based on a deep convolutional neural network. Photographs of 17,560 patients with 1,115 rare disorders were used to define a Clinical Face Phenotype Space, in which distances between cases define syndromic similarity. Here we show that patients can be matched to others with the same molecular diagnosis even when the disorder was not included in the training set. Together with mutation data, GestaltMatcher could not only accelerate the clinical diagnosis of patients with ultra-rare disorders and facial dysmorphism but also enable the delineation of new phenotypes.
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