Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly

<p>Abstract</p> <p>Background</p> <p>Sotos syndrome is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the <it>NSD1 </it>gene, located at 5q35. Sotos syndrome has been described in a number of patients with autism spectrum disorders, suggesting that <it>NSD1 </it>could be involved in other cases of autism and macrocephaly.</p> <p>Methods</p> <p>We screened the <it>NSD1 </it>gene for mutations and deletions in 88 patients with autism spectrum disorders and macrocephaly (head circumference 2 standard deviations or more above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions. Dosage analysis of <it>NSD1 </it>was carried out using multiplex ligation-dependent probe amplification.</p> <p>Results</p> <p>We identified three missense variants (R604L, S822C and E1499G) in one patient each, but none is within a functional domain. In addition, segregation analysis showed that all variants were inherited from healthy parents and in two cases were also present in unaffected siblings, indicating that they are probably nonpathogenic. No partial or whole gene deletions/duplications were observed.</p> <p>Conclusion</p> <p>Our findings suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for <it>NSD1 </it>mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.</p

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival

Evaluating Claims of Early Human Occupation at Chiquihuite Cave, Mexico

Archaeologists working in Mexico recently claimed evidence for pre-Last Glacial Maximum human occupation in the Americas, based on lithic items excavated from Chiquihuite Cave, Zacatecas. Although they provide extensive array of ancillary studies of the cave's chronostratigraphic and paleoenvironmental record, the data they present do not support their central argument, that these lithic items are anthropogenic and represent a unique lithic industry produced by early human occupants. They give limited consideration to the most plausible alternative explanation: that the assemblage is a product of natural processes of disintegration, roof fall, and mass movement of the cave fill, and thus the lithic materials are best explained as geofacts. We assess the evidence by considering the alternative hypotheses (1) that the observed phenomena are artifacts or (2) that they result from natural processes. We conclude that hypothesis 2 is more strongly supported and that Chiquihuite Cave does not represent evidence for the earliest Americans.18 month embargo; published online: 23 October 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Current Understanding of the Earliest Human Occupations in the Americas: Evaluation of Becerra-Valdivia and Higham (2020)

Various chronologies of the earliest Native American occupations have been proposed with varying levels of empirical support and conceptual rigor, yet none is widely accepted. A recent survey of pre-Clovis dated sites (Becerra-Valdivia and Higham 2020) concludes a pre-Last Glacial Maximum (>26,500–19,000 cal yr BP) entry of humans in the Americas, in part based on recent work at Chiquihuite Cave, Mexico. We evaluate the evidence used to develop this inference. To provide clarity, we present three explicit dispersal models for the earliest human dispersals to the Americas: Strict Clovis-First (13,050 cal yr BP), Paleoindian (16,000 cal yr BP, encompassing pre-LGM, preferred by Becerra-Valdivia and Higham (2020)), and we summarize the current genetic and archaeological evidence bearing on each. We regard all purported Pre-Paleoindian sites as equivocal and the Strict Clovis-First model to be equally unsupported at present. We conclude that current data strongly support the Paleoindian Dispersal model, with Native American ancestors expanding into the Americas sometime after 16,000 cal yr BP (and perhaps after 14,800 cal yr BP), consistent with well-dated archaeological sites and with genetic data throughout the western hemisphere. Models of the Americas’ peopling that incorporate Chiquihuite or other claimed Pre-Paleoindian sites remain unsubstantiated.18 month embargo; published online: 23 October 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]