Glucose transporter-1 deficiency syndrome with extreme phenotypic variability in a five-generation family carrying a novel SLC2A1 variant.

BACKGROUND AND PURPOSE: Glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1-DS) is a metabolic disorder due to reduced expression of GLUT1, a glucose transporter of the central nervous system. GLUT1-DS is caused by heterozygous SLC2A1 variants that mostly arise de novo. Here, we report a large family with heterogeneous phenotypes related to a novel SLC2A1 variant. METHODS: We present clinical and genetic features of a five-generation family with GLUT1-DS. RESULTS: The 14 (nine living) affected members had heterogeneous phenotypes, including seizures (11/14), behavioral disturbances (5/14), mild intellectual disability (3/14), and/or gait disabilities (2/14). Brain magnetic resonance imaging revealed hippocampal sclerosis in the 8-year-old proband, who also had drug-responsive absences associated with attention-deficit/hyperactivity disorder. His 52-year-old father, who had focal epilepsy since childhood, developed paraparesis related to a reversible myelitis associated with hypoglycorrhachia. Molecular study detected a novel heterozygous missense variant (c.446C>T) in exon 4 of SLC2A1 (NM: 006516.2) that cosegregated with the illness. This variant causes an amino acid replacement (p.Pro149Leu) at the fourth transmembrane segment of GLUT1, an important domain located at its catalytic core. CONCLUSIONS: Our study illustrates the extremely heterogenous phenotypes in familial GLUT1-DS, ranging from milder classic phenotypes to more subtle neurological disorder including paraparesis. This novel SLC2A1 variant (c.446C>T) provides new insight into the pathophysiology of GLUT1-DS.

3q29 microduplication syndrome: New evidence for the refinement of the critical region.

BACKGROUND: The 3q29 microduplication syndrome is a rare genomic disorder characterized by an extremely variable neurodevelopmental phenotype usually involving a genomic region ranging from 1.6 to 1.76 Mb. A small microduplication of 448.8 Kb containing only two genes was recently described in a patient with a 3q29 microduplication that was proposed as the minimal critical region of overlap of this syndrome. METHODS: Molecular karyotyping (array-CGH) was performed on DNA extracted from peripheral blood samples using Agilent-California USA Human Genome CGH Microarray 4 × 180 K. The proband and his younger brother were further tested with a next generation sequencing (NGS) panel including genes implicated in autism spectrum disorder and in neurodevelopmental disorders. Quantitative real-time PCR was applied to verify the abnormal array-CGH findings. RESULTS: Here, we report on a family with two males with neurodevelopmental disorders and an unaffected sibling with a small 3q29 microduplication (432.8 Kb) inherited from an unaffected mother that involves only two genes: DGL1 and BDH1. The proband had an additional intragenic duplication inherited from the unaffected father. Further testing was negative for Fragile X syndrome and for genes implicated in autism spectrum disorder and in neurodevelopmental disorders. CONCLUSION: To the best of our knowledge, one of the family members here analyzed is the second reported case of a patient carrying a small 3q29 microduplication including only DGL1 and BDH1 genes and without any additional genetic aberration. The recognition of the clinical spectrum in patients with the critical region of overlap associated with the 3q29 duplication syndrome should prove valuable for predicting outcomes and providing more informed genetic counseling to patients with duplications in this region.

7p22.2 Microduplication: A Pathogenic CNV?

Partial duplication of the short arm of chromosome 7 is a rare chromosome rearrangement. The phenotype spectrum associated with this rearrangement is extremely variable even if in the last decade the use of high-resolution microarray technology for the investigation of patients carrying this rearrangement allowed for the identification of the 7p22.1 sub-band causative of this phenotype and to recognize the corresponding 7p22.1 microduplication syndrome. We report two unrelated patients that carry a microduplication involving the 7.22.2 sub-band. Unlike 7p22.1 microduplication carriers, both patients only show a neurodevelopmental disorder without malformations. We better characterized the clinical pictures of these two patients providing insight into the clinical phenotype associated with the microduplication of the 7p22.2 sub-band and support for a possible role of this sub-band in the 7p22 microduplication syndrome.

A new approach to broaden the range of eye colour identifiable by IrisPlex in DNA phenotyping.

IrisPlex system represents the most popular model for eye colour prediction. Based on six polymorphisms this model provides very accurate predictions that strongly depend on the definition of eye colour phenotypes. The aim of the present study was to introduce a new approach to improve eye colour prediction using the well-validated IrisPlex system. A sample of 238 individuals from a Southern Italian population was collected and for each of them a high-resolution image of eye was obtained. By quantifying eye colour variation into CIELAB space several clustering algorithms were applied for eye colour classification. Predictions with the IrisPlex model were obtained using eye colour categories defined by both visual inspection and clustering algorithms. IrisPlex system predicted blue and brown eye colour with high accuracy while it was inefficient in the prediction of intermediate eye colour. Clustering-based eye colour resulted in a significantly increased accuracy of the model especially for brown eyes. Our results confirm the validity of the IrisPlex system for forensic purposes. Although the quantitative approach here proposed for eye colour definition slightly improves its prediction accuracy, further research is still required to improve the model particularly for the intermediate eye colour prediction.

Rare copy number variants in ASTN2 gene in patients with neurodevelopmental disorders.

INTRODUCTION: In humans the normal development of cortical regions depends on the complex interactions between a number of proteins that promote the migrations of neuronal precursors from germinal zones and assembly into neuronal laminae. ASTN2 is one of the proteins implicated in such a complex process. Recently it has been observed that ASTN2 also regulates the surface expression of multiple synaptic proteins resulting in a modulation of synaptic activity. Several rare copy number variants (CNVs) in ASTN2 gene were identified in patients with neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), attention deficit-hyperactivity disorders and intellectual disability. METHODS: By using comparative genomic hybridization array technology, we analyzed the genomic profiles of five patients of three unrelated families with NDDs. Clinical diagnosis of ASD was established according to the Statistical Manual of Mental Disorders, Fifth Edition (APA 2013) criteria. RESULTS: We identified new rare CNVs encompassing ASTN2 gene in three unrelated families with different clinical phenotypes of NDDs. In particular, we identified a deletion of about 70 Kb encompassing intron 19, a 186 Kb duplication encompassing the sequence between the 5'-end and the first intron of the gene and a 205 Kb deletion encompassing exons 6-11. CONCLUSION: The CNVs reported here involve regions not usually disrupted in patients with NDDs with two of them affecting only the expression of the long isoforms. Further studies will be needed to analyze the impact of these CNVs on gene expression regulation and to better understand their impact on the protein function.

Peripheral LPS administrations up-regulate Fas and FasL on brain microglial cells: a brain protective or pathogenic event?

We evaluated the effect of single or repeated intraperitoneal daily LPS injections on expression of Fas/FasL system within the brain. Results obtained, utilizing real-time quantitative RT-PCR, show that, while a bolus injection of LPS robustly increases hippocampal Fas, but not FasL, mRNA expression, repeated LPS administrations also induce FasL up-regulation. Immunofluorescence studies demonstrated, in turn, an increased number of Fas and FasL immunoreactive microglial cells within the brain parenchyma. The increase in FasL immunoreactivity was, in contrast to Fas, still evident 2 weeks following LPS wash-out. At all times, no Fas-positive immunoreactive neurons nor TUNEL-positive resident brain cells were observed. Collectively, these data provide further support for the existence of innate immune responses in brain and, in addition, raise the possibility that Fas and FasL are, within the brain parenchyma, differentially regulated.