The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene encodes an InsP₃-gated calcium channel that modulates intracellular Ca²⁺ release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the ITPR1 gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet. With the aim of describing ITPR1-related neuroimaging findings, the brain MRI of 14 patients with ITPR1 variants (11 SCA29, 1 SCA15, and 2 Gillespie) were reviewed by expert neuroradiologists. To further evaluate the role of superior vermian and hemispheric cerebellar atrophy as a clue for the diagnosis of ITPR1-related conditions, the ITPR1 gene was sequenced in 5 patients with similar MRI pattern, detecting pathogenic variants in 4 of them. Considering the whole cohort, a distinctive neuroradiological pattern consisting in superior vermian and hemispheric cerebellar atrophy was identified in 83% patients with causative ITPR1 variants, suggesting this MRI finding could represent a hallmark for ITPR1-related disorders.

Background/Objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis. Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools. Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype–phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome. Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes.

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.

Biallelic pathogenic variants in TTC21B, encoding the retrograde intraflagellar transport protein IFT139, are a known cause of renal and skeletal ciliopathies. Single heterozygous variants in this gene were found to be enriched in a cohort of patients with various ciliopathy phenotypes, including three individuals with Joubert syndrome (JS), a neurodevelopmental ciliopathy characterized by a peculiar cerebellar and brainstem malformation. It was then suggested that TTC21B could act as a modifier gene for ciliopathies. Here we report a patient homozygous for the hypomorphic founder variant p.Pro209Leu in TTC21B , who presented typical neurological and neuroradiological features of JS, along with mild renal dysplasia and retinal dystrophy. To our knowledge, this is the first case reported with molecularly confirmed JS caused by biallelic pathogenic variants in TTC21B, expanding the spectrum of TTC21B ‐associated ciliopathies, further highlighting the complex genetic basis of ciliopathies.

Biallelic loss‐of‐function variants in TXNDC15 are a known cause of the perinatally lethal ciliopathy Meckel syndrome (MKS). TXNDC15 encodes an endoplasmic reticulum (ER)‐resident thioredoxin‐domain protein required for ciliary transition zone integrity. Many ciliopathy genes show a spectrum of severity, producing a clinical continuum from lethal MKS to the less severe Joubert syndrome (JS). Using genome and exome sequencing analysis, we identified four unrelated children with JS who harbor rare biallelic variants in TXNDC15. In contrast to the biallelic truncating variants typical of MKS, all individuals with JS carried a missense variant in trans with a truncating variant. Three of four missense variants cluster within the functionally critical thioredoxin domain. In silico structural modeling using AlphaFold and variant effect prediction (AlphaMissense, DynaMut2) support a deleterious effect on protein stability and function for the majority of these missense variants. This work expands the phenotypic spectrum of TXNDC15 ‐related ciliopathies to include JS. All four individuals carried a missense allele in trans with a truncating allele. Our findings underscore the importance of including TXNDC15 in the genetic diagnosis of JS.