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Bardet-Biedl syndrome (BBS; MIM 209900) is a recessive heterogeneous ciliopathy characterized by retinitis pigmentosa (RP), postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. So far, 20 BBS genes have been identified, with the last reported ones being found in one or very few families. Whole-exome sequencing was performed in a consanguineous family in which two affected children presented typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism and cognitive impairment) without any mutation identified in known BBS genes at the time of the study. We identified a homozygous splice-site mutation (NM_015662.2: c.4428+3A>G) in both affected siblings in the last reported BBS gene, namely, Intraflagellar Transport 172 Homolog (IFT172). Familial mutation segregation was consistent with autosomal recessive inheritance. IFT172 mutations were initially reported in Jeune and Mainzer-Saldino syndromes. Recently, mutations have also been found in isolated RP and Bardet-Biedl-like ciliopathy. This is the second report of IFT172 mutations in BBS patients validating IFT172 as the twentieth BBS gene (BBS20). Moreover, another IFT gene, IFT27, was already associated with BBS, confirming the implication of IFT genes in the pathogenesis of BBS.

Background Bardet–Biedl syndrome (BBS) is a recessive and genetically heterogeneous ciliopathy characterised by retinitis pigmentosa, obesity, kidney dysfunction, postaxial polydactyly, behavioural dysfunction and hypogonadism. 7 of the 17 BBS gene products identified to date assemble together with the protein BBIP1/BBIP10 into the BBSome, a protein complex that ferries signalling receptors to and from cilia. Methods and results Exome sequencing performed on a sporadic BBS case revealed for the first time a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. This mutation is pathogenic since no BBIP1 protein could be detected in fibroblasts from the patient, and BBIP1[Leu58*] is unable to associate with the BBSome subunit BBS4. Conclusions These findings identify BBIP1 as the 18th BBS gene (BBS18) and suggest that BBSome assembly may represent a unifying pathomechanism for BBS.

BackgroundPathogenic gain-of-function or dominant-negative effect missense variations in ACTB are associated with a neurodevelopmental disorder characterised by intellectual disability (ID), seizures, sensorineural hearing loss, cerebral, renal and ocular abnormalities and dysmorphic features (Baraitser-Winter cerebrofrontofacial syndrome). ACTB encodes beta-actin, a highly conserved protein involved in cell motility, structure and integrity. Deletions including ACTB, and, more rarely, single-nucleotide loss-of-function variants in ACTB have been described in patients with a distinct phenotype including developmental delay, ID, microcephaly, growth restriction, cardiac and renal abnormalities and dysmorphic features.MethodsWe collected 14 individuals and 1 fetus carrying a heterozygous deletion including ACTB, and 4 individuals with a heterozygous truncating variant. Genotypic and phenotypic data were analysed. Furthermore, a comprehensive review of all cases reported to date was also undertaken.ResultsTwelve out of 17 individuals presented with ID, and 3 out of 17 with learning disabilities. Speech delay and behavioural abnormalities were observed in 15 out of 17 and 12 out of 17 individuals, respectively, motor delay in 9 out of 17 and growth restriction in 9 out of 18. Most of the individuals (13/18) had recognisable dysmorphic features. 11 anomalies were de novo, except for 1 deletion inherited from the mother. The size of the deletion varied from 125 kb to 1.6 Mb and could result from a fork stalling and template switching.ConclusionThis study allowed us to better characterise the phenotype associated with the haploinsufficiency of ACTB, underlying the high prevalence of neurodevelopmental disorders (ID, speech and motor delay, behavioural abnormalities) and growth restriction in this recognisable syndrome.

The ubiquitin–proteasome system degrades ubiquitin‐modified proteins to maintain protein homeostasis and to control signalling. Whole‐genome sequencing of patients with severe deafness and early‐onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development. Synopsis Whole genome sequencing in a large consanguineous family with neurosensory syndrome revealed a unique homozygous deep intronic pathogenic variant in PSMC3, encoding one of the proteasome subunit. Further in vitro and in vivo analyses confirmed the pathogenicity of the PSMC3 mutation. This is the first implication of a 26S proteasome AAA‐ATPase of the 19S proteasome regulatory complex in a neurosensorial disease with early onset cataract and deafness. Functional analysis using patient's cells revealed a pathogenic mechanism with proteasome impairment resulting in proteotoxic stress with over‐activation of the TCF11/Nrf1 transcriptional pathway. Zebrafish model reproduces the human phenotype with cataract and ear malformations. PSMC3 plays a major role in inner ear, lens and central nervous system development. These results expand our knowledge on the genetic background of the emerging proteasomopathy. Graphical Abstract Whole genome sequencing in a large consanguineous family with neurosensory syndrome revealed a unique homozygous deep intronic pathogenic variant in PSMC3, encoding one of the proteasome subunit. Further in vitro and in vivo analyses confirmed the pathogenicity of the PSMC3 mutation.

Ciliopathies are a group of diseases that affect kidney and retina among other organs. Here, we identify a missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15 ) in a family with a ciliopathy phenotype. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts, as well as ciliary processes in zebrafish. Furthermore, we demonstrate its interaction with the golgin GM130 and its localization to the Golgi. The VPS15-R998Q patient mutation impairs Golgi trafficking functions in humanized yeast cells. Moreover, in VPS15-R998Q patient fibroblasts, the intraflagellar transport protein IFT20 is not localized to vesicles trafficking to the cilium but is restricted to the Golgi. Our findings suggest that at the Golgi, VPS15 and GM130 form a protein complex devoid of VPS34 to ensure the IFT20-dependent sorting and transport of membrane proteins from the cis -Golgi to the primary cilium. VPS15 is known as a VPS34-associated protein that functions in intracellular trafficking and autophagy. Here the authors identify a role for VPS15 in ciliopathy and ciliary phenotypes, and show that it interacts with GM130 and functions in IFT20-dependent cis -Golgi to cilium trafficking.

Recessive mutations in PYROXD1 , encoding an oxidoreductase, were recently reported in families with congenital myopathy or limb-girdle muscular dystrophy. Here we describe three novel PYROXD1 families at the clinical, histological, and genetic level. Histological analyses on muscle biopsies from all families revealed fiber size variability, endomysial fibrosis, and muscle fibers with multiple internal nuclei and cores. Further characterization of the structural muscle defects uncovered aggregations of myofibrillar proteins, and provided evidence for enhanced oxidative stress. Sequencing identified homozygous or compound heterozygous PYROXD1 mutations including the first deep intronic mutation reinforcing a cryptic donor splice site and resulting in mRNA instability through exonisation of an intronic segment. Overall, this work expands the PYROXD1 mutation spectrum, defines and specifies the histopathological hallmarks of the disorder, and indicates that oxidative stress contributes to the pathomechanism. Comparison of all new and published cases uncovered a genotype/phenotype correlation with a more severe and early-onset phenotypic presentation of patients harboring splice mutations resulting in reduced PYROXD1 protein levels compared with patients carrying missense mutations.

Ciliopathies are rare genetic disorders caused by dysfunction of the primary or motile cilia. Their mode of inheritance is mostly autosomal recessive with biallelic pathogenic variants inherited from the parents. However, exceptions exist such as uniparental disomy (UPD) or the appearance of a de novo pathogenic variant in trans of an inherited pathogenic variant. These two genetic mechanisms are expected to be extremely rare, and few data are available in the literature, especially regarding ciliopathies. In this study, we investigated 940 individuals (812 families) with a suspected ciliopathy by Sanger sequencing, high-throughput sequencing and/or SNP array analysis and performed a literature review of UPD and de novo variants in ciliopathies. In a large cohort of 623 individuals (511 families) with a molecular diagnosis of ciliopathy (mainly Bardet-Biedl syndrome and Alström syndrome), we identified five UPD, revealing an inherited pathogenic variant and five pathogenic variants of de novo appearance (in trans of another pathogenic variant). Moreover, from these ten cases, we reported 15 different pathogenic variants of which five are novel. We demonstrated a relatively high prevalence of UPD and de novo variants in a large cohort of ciliopathies and highlighted the importance of identifying such rare genetic events, especially for genetic counseling.

Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, BBS5 is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia. This study reports on a European BBS5 patient with a severe BBS phenotype. Genetic analysis was performed using multiple next-generation sequencing (NGS) tests (targeted exome, TES and whole exome, WES), and biallelic pathogenic variants could only be identified using whole-genome sequencing (WGS), including a previously missed large deletion of the first exons. Despite the absence of family samples, the biallelic status of the variants was confirmed. The BBS5 protein’s impact was confirmed on the patient’s cells (presence/absence and size of the cilium) and ciliary function (Sonic Hedgehog pathway). This study highlights the importance of WGS and the challenge of reliable structural variant detection in patients’ genetic explorations as well as functional tests to assess a variant’s pathogenicity.

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.