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Alazami syndrome is a rare disorder with an autosomal recessive inheritance caused by pathogenic biallelic variants in the LARP7 gene. Clinically, it is mainly characterized by short stature, intellectual disability, and dysmorphic facial features. However, the phenotype is not yet well-defined because less than 50 cases have been described to date. Here, we report three new patients from two unrelated Spanish families who, in addition to the defined features of Alazami syndrome, also exhibit unique features that broaden the phenotypic spectrum of the syndrome. Moreover, we describe the novel frameshift variant c.690_699delins27 in the LARP7 gene, in which loss of function is a known mechanism of Alazami syndrome.

Objective:SQSTM1-variants associated with frontotemporal lobar degeneration have been described recently. In this study, we investigated a heterozygous in-frame duplication c.436_462dup p. (Pro146_Cys154dup) in the SQSTM1 gene in a family with a new phenotype characterized by a personality disorder and behavioral variant frontotemporal dementia (bvFTD). We review the literature on frontotemporal dementia (FTD) associated with SQSTM1. Methods: The index case and relatives were described, and a genetic study through Whole Exome Sequencing was performed. The literature was reviewed using Medline and Web of Science. Case reports, case series, and cohort studies were included if they provided information on SQSTM1 mutations associated with FTD. Results: Our patient is a 70-year-old man with a personality disorder since youth, familial history of dementia, and personality disorders with a 10-year history of cognitive decline and behavioral disturbances. A diagnosis of probable bvFTD was established, and the in-frame duplication c.436_462dup in the SQSTM1 gene was identified. Segregation analysis in the family confirmed that both affected sons with personality disorder were heterozygous carriers, but not his healthy 65-year-old brother. A total of 14 publications about 57 patients with SQSTM1-related FTD were reviewed, in which the bvFTD subtype was the main phenotype described (66.6%), with a predominance in men (63%) and positive family history in 61.4% of the cases. Conclusions: We describe a heterozygous in-frame duplication c.436_462dup p.(Pro146_Cys154dup) in the SQSTM1 gene, which affects the zinc-finger domain of p62, in a family with a personality disorder and bvFTD, expanding the genetics and clinical phenotype related to SQSTM1. © 2021 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion.

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44, 75%) compared to CMA (9/44, 20.4%) or FMR1 testing (2/44, 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.

The presence of metabolic syndrome (MS) per se or its separated components in HIV-infected patients contributes to an accelerated aging and increased cardiovascular risk. Gut microbiota (GM) dysbiosis has been linked with chronic inflammation associated with MS in a general non-infected population. However, no studies concerning GM have been performed in HIV-infected patients with MS. The aim of this study was to analyze bacterial translocation, inflammation, and GM composition in HIV-infected patients with and without MS. A total of 51 HIV-infected patients were recruited and classified according to the presence of MS (40 patients without MS and 11 with MS). Markers of bacterial translocation, inflammation, and cardiovascular risk were measured and GM was analyzed using 16S rRNA gene deep sequencing. No differences were observed among both HIV-infected groups in the bacterial translocation markers LBP and sCD14. A tendency to increase the inflammatory markers IL-6 (p = 0.069) and MCP-1 (p = 0.067) was observed in those patients suffering from MS. An increase in the cardiovascular risk markers PAI-1 (p = 0.007) and triglycerides/HDL cholesterol ratio (p

The haploinsufficiency of the methyl-binding domain protein 5 (MBD5) gene has been identified as the determinant cause of the neuropsychiatric disorders grouped under the name MBD5-neurodevelopment disorders (MAND). MAND includes patients with intellectual disability, behavioral problems, and seizures with a static clinical course. However, a few reports have suggested regression. We describe a non-intellectually disabled female, with previous epilepsy and personality disorder, who developed early-onset dementia. The extensive etiologic study revealed a heterozygous nonsense de novo pathogenic variant in the MBD5 gene. This finding could support including the MBD5 gene in the study of patients with atypical early-onset dementia. © 2021 - IOS Press. All rights reserved.

Neurofibromatosis type I (NF1) is one of the most common genetic disorders in humans. NF1, a tumor predisposition syndrome, is caused by heterozygous pathogenic variants in the NF1 gene. Molecular genetic testing of NF1 is complex, especially because of the presence of a high number of partial pseudogenes, some of them with a high percentage of sequence identity. In this study, we have analyzed the largest cohort of NF1 Spanish patients (150 unrelated individuals suspected of having NF1 and 53 relatives, making a total of 203 individuals). Mutation analysis of the entire coding region was performed in all unrelated index patients. Additionally, the Multiplex Ligation-dependent Probe Amplification (MLPA) test of the NF1 gene and SPRED1 gene analysis (sequencing and MLPA test) was performed in some of the negative patients for NF1 point mutations. When fulfilling the National Institutes of Health (NIH) criterion for the clinical diagnosis of NF1, the detection rate was 79%. Among the 80 genetically confirmed NF1 probands, we detected 69 different pathogenic variants. Two mutations (3%) were gross deletions of the whole gene, the remaining 78 mutations (97%) were small changes spread among all NF1 exons. Among these 69 different mutations detected, 42 mutations were described elsewhere, and 27 mutations were novel mutations. When segregation was studied, 67% of mutations resulted de novo variants. No genetic mosaicism was detected on patients' parents.

The analysis of genes involved in hereditary spherocytosis, by next-generation sequencing in two patients with clinical diagnosis of the disease, showed the presence of the c.1795+1G>A mutation in the SPTB gene. cDNA amplification then revealed the occurrence of a consequent aberrant mRNA isoform produced from the activation of a cryptic 5′-splice site and the creation of a newly 3′-splice site. The mechanisms by which these two splice sites are used as a result of the same mutation should be analyzed in depth in further studies.