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Developmental delay/intellectual disabilities, speech disturbance, pre- and postnatal growth retardation, microcephaly, signs of ectodermal dysplasia, and genital malformations in males (hypospadias) represent the phenotypic core of the recent emerging 19q13.11 deletion syndrome. Using array-CGH for genome-wide screening we detected an interstitial deletion of chromosome band 19q13.11 in two patients exhibiting the recognizable pattern of malformations as described in other instances of this submicroscopic genomic imbalance. The deletion detected in our patients has been compared with previously reported cases leading to the refinement of the minimal overlapping region (MOR) for this microdeletion syndrome to 324 kb. This region encompasses five genes: four zinc finger (ZNF) genes belonging to the KRAB-ZNF subfamily (ZNF302, ZNF181, ZNF599, and ZNF30) and LOC400685. On the basis of our male patient 1 and on further six male cases of the literature, we also highlighted that larger 19q13.11 deletions including the Wilms tumor interacting protein (WTIP) gene, proximal to the MOR, results in hypospadias making this gene a possible candidate for this genital abnormality due to its well-known interaction with WT1. Although the mechanism underlying the phenotypic effects of copy number alterations involving KRAB-ZNF genes at 19q13.11 has not clearly been established, we suggest their haploinsufficiency as the most likely candidate for the phenotypic core of the 19q13.11 deletion syndrome. In addition, we hypothesized WTIP gene haploinsufficiency as responsible for hypospadias.

Background: The advent of next-generation sequencing (NGS) techniques in clinical practice led to a significant advance in gene discovery. We aimed to describe diagnostic yields of a “dynamic” exome-based approach in a cohort of patients with epilepsy associated with neurodevelopmental disorders. Methods: We conducted a retrospective, observational study on 72 probands. All patients underwent a first diagnostic level of a 135 gene panel, a second of 297 genes for inconclusive cases, and finally, a whole-exome sequencing for negative cases. Diagnostic yields at each step and cost-effectiveness were the objects of statistical analysis. Results: Overall diagnostic yield in our cohort was 37.5%: 29% of diagnoses derived from the first step analysis, 5.5% from the second step, and 3% from the third. A significant difference emerged between the three diagnostic steps (p < 0.01), between the first and second (p = 0.001), and the first and third (p << 0.001). The cost-effectiveness plane indicated that our exome-based “dynamic” approach was better in terms of cost savings and higher diagnostic rate. Conclusions: Our findings suggested that “dynamic” NGS techniques applied to well-phenotyped individuals can save both time and resources. In patients with unexplained epilepsy comorbid with NDDs, our approach might maximize the number of diagnoses achieved.

The primary anatomical defect leading to periventricular nodular heterotopia occurs within the neural progenitors along the neuroepithelial lining of the lateral ventricles and results from a defect in the initiation of neuronal migration, following disruption of the neuroependyma and impaired neuronal motility. Growing evidence indicates that the FLNA-dependent actin dynamics and regulation of vesicle formation and trafficking by activation of ADP-ribosylation factors (ARFs) can play an important role in this cortical malformation. We report the first inherited variant of ARF1 in a girl with intellectual disability and periventricular nodular heterotopia who inherited the variant from the father with previously undiagnosed single nodular heterotopia and mild clinical expression. Additionally, both patients presented some features suggestive of hypohidrotic ectodermal dysplasia. These clinical features showed similarities to those of three previously reported cases with ARF1 missense variants, confirming that haploinsufficiency of this gene causes a recognisable neurological disorder with abnormal neuronal migration and variable clinical expressivity.

Joubert syndrome (JS) is an inherited neurodevelopmental ciliopathy with wide clinical and genetic heterogeneity, whose paradigmatic sign is a peculiar cerebellar and brainstem malformation known as the ‘molar tooth sign’. Recessive pathogenic variants in the HYLS1 gene are associated with hydrolethalus syndrome (HLS), a severe disorder characterised by multiple developmental defects leading to intrauterine or perinatal death. However, HYLS1 biallelic variants were also reported in three individuals with JS.Here, we report a fourth patient with a purely neurological JS carrying two compound heterozygous missense variants in the HYLS1 gene. Notably, while all patients with lethal HLS had both variants falling within the highly conserved HYLS-1 Box, the four patients with milder JS phenotype featured at least one variant external to this evolutionary conserved domain, suggesting a possible correlation between the mutation site and the severity of the phenotype.

RNU4ATAC is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic RNU4ATAC pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the ‘molar tooth sign’ (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four RNU4ATAC variants (n.16G>A, n.51G>A, n.13C>T and n.30G>A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and RNU4ATAC-related skeletal disorders.These findings expand the phenotypic spectrum of RNU4ATAC-related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.

Joubert syndrome (JS) is a genetically heterogeneous neurodevelopmental ciliopathy. Despite exome sequencing (ES), several patients remain undiagnosed. This study aims to increase the diagnostic yield by uncovering cryptic variants through targeted ES reanalysis. We first focused on 26 patients in whom ES only disclosed heterozygous pathogenic coding variants in a JS gene. We reanalyzed raw ES data searching for copy number variants (CNVs) and intronic variants affecting splicing. We validated CNVs through real-time PCR or chromosomal microarray, and splicing variants through RT-PCR or minigenes. Cryptic variants were then searched in additional 44 ES-negative JS individuals. We identified cryptic “second hits” in 14 of 26 children (54%) and biallelic cryptic variants in 3 of 44 (7%), reaching a definite diagnosis in 17 of 70 (overall diagnostic gain 24%). We show that CNVs and intronic splicing variants are a common mutational mechanism in JS; more importantly, we demonstrate that a significant proportion of such variants can be disclosed simply through a focused reanalysis of available ES data, with a significantly increase of the diagnostic yield especially among patients previously found to carry heterozygous coding variants in the KIAA0586 , CC2D2A and CPLANE1 genes.

Background/Objectives: Hereditary spastic paraplegias (HSPs) comprise a heterogenous spectrum of rare neurogenetic disorders predominantly characterized by progressive spasticity and weakness of the lower extremities. Among autosomal-dominant forms of HSP, molecular defects in the SPAST gene—particularly those associated with the SPG4 subtype—represent the most frequent genetic cause. SPAST encodes spastin, a microtubule-severing ATPase, crucial for cytoskeletal remodeling, neuronal connectivity, and intracellular trafficking. Disruption of spastin function can impair neurite outgrowth and synaptic formation, processes increasingly implicated in neurodevelopmental disorders (NDDs). Methods: We conducted a comprehensive clinical, neurological, and dysmorphological evaluation of a 4-year-old male. Standardized neuropsychological assessments were administered. Whole-exome sequencing (WES) was performed to identify underlying genetic causes. EEG and 3T-brain MRI were also acquired. Results: The proband harbored two novel de novo heterozygous missense variants in cis of the SPAST gene, displaying the typical features of early-onset and complex HSP, in addition to global developmental delay and severe autism spectrum disorder (ASD), an underexplored manifestation in this rare genetic disorder. Conclusions: These findings broaden the clinical and mutational spectrum of SPG4, underscoring the importance of considering SPAST gene analysis in patients with ASD in the early years of life and early motor delay, even in the presence of only subtle pyramidal signs. We advocate for comprehensive neuropsychiatric assessment in the diagnostic pathway of early-onset complex HSP presentations and support further investigation into the role of spastin in neuronal connectivity.

BackgroundJoubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the ‘molar tooth sign’. Over 40 JS-associated genes are known, accounting for two-thirds of cases.MethodsWhile most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known ‘founder variants’ in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA.ResultsAll variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant (TMEM216 c.218G>T) was significantly enriched in American compared with European patients with JS, while MKS1 c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes.Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from a MKS1 c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from a KIAA0586 c.428delG healthy homozygote.ConclusionThis study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants.

BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%–75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.MethodsWe reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.ResultsHeterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.ConclusionHeterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.