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While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.58 × 10(-11), odds ratio = 4.59), dyslexia (p = 3.81 × 10(-18), odds ratio = 14.45), or controls (p = 2.75 × 10(-17), odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4 × 10(-6), odds ratio = 6) or ID (16%, p = 3.55 × 10(-12), odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).

Background Individuals with the 2p15p16.1 microdeletion syndrome share a complex phenotype including neurodevelopmental delay, brain malformations, microcephaly, and autistic behavior. The analysis of the shortest region of overlap (SRO) between deletions in ~ 40 patients has led to the identification of two critical regions and four strongly candidate genes ( BCL11A, REL, USP34 and XPO1 ). However, the delineation of their role in the occurrence of specific traits is hampered by their incomplete penetrance. Objective To better delineate the role of hemizygosity of specific regions in selected traits by leveraging information both from penetrant and non − penetrant deletions. Methods Deletions in patients that do not present a specific trait cannot contribute to delineate the SROs. We recently developed a probabilistic model that, by considering also the non − penetrant deletions, allows a more reliable assignment of peculiar traits to specific genomic segments. We apply this method adding two new patients to the published cases. Results Our results delineate an intricate pattern of genotype − phenotype correlation where BCL11A emerges as the main gene for autistic behavior while USP34 and/or XPO1 haploinsufficiency are mainly associated with microcephaly, hearing loss and IUGR. BCL11A, USP34 and XPO1 genes are broadly related with brain malformations albeit with distinct patterns of brain damage. Conclusions The observed penetrance of deletions encompassing different SROs and that predicted when considering each single SRO as acting independently, may reflect a more complex model than the additive one. Our approach may improve the genotype/phenotype correlation and may help to identify specific pathogenic mechanisms in contiguous gene syndromes.

Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC) and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders.

Germline mutations of and are associated with a defined lifetime risk of breast (BC), ovarian (OC) and other cancers. Testing genes is pivotal to assess individual risk, but also to pursue preventive approaches in healthy carriers and tailored treatments in tumor patients. The prevalence of and alterations varies broadly across different geographic regions and, despite data about pathogenic variants among Sicilian families exist, studies specifically addressing eastern Sicily population are lacking. The aim of our study was to investigate the incidence and distribution of pathogenic germline alterations in a cohort of BC patients from eastern Sicily and to evaluate their associations with specific BC features. Mutational status was assessed in a cohort of 389 BC patients, using next generation sequencing. The presence of alterations was correlated with tumor grading and proliferation index. Overall, 35 patients (9%) harbored a pathogenic variant, 17 (49%) in and 18 (51%) in alterations were prevalent among triple negative BC patients, whereas mutations were more common in subjects with luminal B BC. Tumor grading and proliferation index were both significantly higher among subjects with variants compared to non-carriers. Our findings provide an overview about mutational status among BC patients from eastern Sicily and confirm the role of NGS analysis to identify hereditary BC patients. Overall, these data are consistent with previous evidences supporting screening to properly prevent and treat cancer among mutation carriers.

Background Emerging evidence suggesting a possible link between the PPP5C gene (protein phosphatase 5 catalytic subunit; OMIM#600658) and developmental and epileptic encephalopathy (DEE, OMIM#308350), although the clinical significance of pathogenic variants in this gene remains unclear. PPP5C is a member of the protein phosphatase catalytic subunit family, which is involved in various signaling pathways governing cell growth, differentiation, and responses to hormonal signals or cellular stress. To date, only one case with a PPP5C variant has been reported, associated with a severe neurological phenotype, including microcephaly, failure to thrive, and early-onset seizures. Results We report a 12-year-old girl affected by epilepsy and learning disorders. At the age of five, she presented convulsive status epilepticus with respiratory failure at onset and she started anticonvulsant therapy with Levetiracetam with a significant improvement. Genetic analysis revealed a de novo heterozygous missense variant of PPP5C gene (c.202 C > T: p.Arg68Cys ), which had not been previously described in the literature. Conclusion This case expands the phenotypic spectrum associated with PPP5C variants, highlighting the potential role of this gene inneurological disorders. Our findings may provide some valuable insights into the spectrum of phenotypic manifestations linked to this gene less investigated in neuropediatrics.

Background: The SARS-CoV-2 virus has assumed considerable importance during the COVID-19 pandemic. Its mutation rate is high, involving the spike (S) gene and thus there has been a rapid spread of new variants. Herein, we describe a rapid, easy, adaptable, and affordable workflow to uniquely identify all currently known variants through as few analyses. Our method only requires two conventional PCRs of the S gene and two Sanger sequencing reactions, and possibly another PCR/sequencing assay on a N gene portion to identify the B.1.160 lineage. Methods: We selected an S gene 1312 bp portion containing a set of SNPs useful for discriminating all variants. Mathematical, statistical, and bioinformatic analyses demonstrated that our choice allowed us to identify all variants even without looking for all related mutations, as some of them are shared by different variants (e.g., N501Y is found in the Alpha, Beta, and Gamma variants) whereas others, that are more informative, are unique (e.g., A57 distinctive to the Alpha variant). Results: A “weight” could be assigned to each mutation that may be present in the selected portion of the S gene. The method’s robustness was confirmed by analyzing 80 SARS-CoV-2-positive samples. Conclusions: Our workflow identified the variants without the need for whole-genome sequencing and with greater reliability than with commercial kits.

Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein highly expressed in neurons that is involved in transcriptional modulation and chromatin remodeling. Mutations in MECP2 in females are associated with Rett syndrome, a neurological disorder characterized by a normal neonatal period, followed by the arrest of development and regression of acquired skills. Although it was initially thought that MECP2 pathogenic mutations in males were not compatible with life, starting from 1999 about 60 male patients have been identified and their phenotype varies from severe neonatal encephalopathy to mild intellectual disability. Targeted next-generation sequencing of a panel of intellectual disability related genes was performed on two unrelated male patients, and two missense variants in MECP2 were identified (p.Gly185Val and p.Arg167Trp). These variants lie outside the canonical methyl-CpG-binding domain and transcription repression domain domains, where the pathogenicity of missense variants is more difficult to establish. In both families, variants were found in all affected siblings and were inherited from the asymptomatic mother, showing skewed X-chromosome inactivation. We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability.

Background It has been known for more than 30 years that balanced translocations, especially if de novo, can associate with congenital malformations and / or neurodevelopmental disorders, following the disruption of a disease gene or its cis-regulatory elements at one or both breakpoints. Case presentation We describe a 10-year-old girl with a non-specific neurodevelopmental disorder characterized by moderate intellectual disability (ID), gross motor clumsiness, social and communication deficits. She carries a de novo reciprocal translocation between chromosomes 1q43 and 22q13.3, the latter suggesting the involvement of SHANK3. Indeed, its haploinsufficiency associates with Phelan-McDermid Syndrome, whose main symptoms are characterized by global developmental delay and absent or severely delayed expressive speech. A deep molecular approach, including next-generation sequencing of SHANK3 locus, allowed demonstrating the breakage of RYR2 and SHANK3 on the derivative chromosomes 1 and 22 respectively, and the formation of two fusion genes SHANK3-RYR2 and RYR2-SHANK3 with concomitant cryptic deletion of 3.6 and 4.1 kilobases at translocation junction of both derivatives chromosomes 22 and 1, respectively. Conclusions Although the interruption of SHANK3 accounts for the patient’s psychomotor retardation and autism-like behavior, we do not exclude that the interruption of RYR2 may also have a role on her disorder, or result in further pathogenicity in the future. Indeed, RYR2 that has a well-established role in the etiology of two autosomal dominant adulthood cardiac disorders (#600996 and #604772) is also expressed in the brain (cerebellum, hippocampus, and cerebral cortex) and about half of RYR2 mutation carriers present late onset primary generalized epilepsy without cardiac arrhythmogenic disorders. Moreover, RYR2 variants have also been sporadically reported in individuals with early onset schizophrenia or ID, and its constraint values suggest intolerance to loss-of-function. This study not only confirms the usefulness of the molecular mapping of de novo balanced rearrangements in symptomatic individuals, but also underscores the need for long-term clinical evaluation of the patients, for better evaluating the pathogenicity of the chromosomal breakpoints.

This study describes two siblings from consanguineous parents who exhibit intellectual disability, microcephaly, photosensitivity, bilateral sensorineural hearing loss, numerous freckles, and other clinical features that suggest a potential disruption of the nucleotide excision repair (NER) pathway. Whole exome sequencing (WES) identified a novel homozygous missense variant in the ERCC4 gene, which was predicted to be pathogenic. However, a subsequent peculiar audiometric finding prompted further investigation, revealing a homozygous deletion in the OTOA gene linked to neurosensorial hearing loss. Both variants were located within a run of homozygosity (ROH) on chromosome 16p13.12-p12.2, implicating a complex genetic basis for the observed phenotype. While this study reports a potentially novel ERCC4 variant, it underscores the importance of comprehensive analysis and deep phenotyping in WES data to improve diagnostic accuracy. Our findings advocate for an expanded approach in WES analysis, ensuring more precise diagnoses and improved genetic counseling, particularly when specialized tests for structural variant analysis are unavailable.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A ( DYRK1A ) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations ( P =0.00851) and an excess of de novo mutations ( P =2.53 × 10 −10 ) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel ( n =5) and recontacted ( n =3) cases with previous case reports, including larger CNV and translocation events ( n =7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.