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Michaela Auer-Grumbach and colleagues report that missense alterations in the N-terminal ankyrin domain of TRPV4 underlie three distinct autosomal dominant disorders of the peripheral nervous system. Alterations in other regions of TRPV4 have been shown to underlie a family of autosomal dominant skeletal dysplasias, underscoring the marked clinical heterogeneity associated with mutations in this channel. Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca 2+ influx was substantially reduced even after stimulation with 4αPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation, leading to reduced surface expression of functional TRPV4 channels.

Background Terminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the project is to improve the surveillance of patients with chromosome 6 aberrations and the support for their families by increasing the available information about these rare aberrations. This parent-driven research project makes use of information collected directly from parents via a multilingual online questionnaire. Here, we report our findings on 93 individuals with terminal 6q deletions and 11 individuals with interstitial 6q26q27 deletions, a cohort that includes 38 newly identified individuals. Results Using this cohort, we can identify a common terminal 6q deletion phenotype that includes microcephaly, dysplastic outer ears, hypertelorism, vision problems, abnormal eye movements, dental abnormalities, feeding problems, recurrent infections, respiratory problems, spinal cord abnormalities, abnormal vertebrae, scoliosis, joint hypermobility, brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures, hypotonia, ataxia, torticollis, balance problems, developmental delay, sleeping problems and hyperactivity. Other frequently reported clinical characteristics are congenital heart defects, kidney problems, abnormalities of the female genitalia, spina bifida, anal abnormalities, positional foot deformities, hypertonia and self-harming behaviour. The phenotypes were comparable up to a deletion size of 7.1 Mb, and most features could be attributed to the terminally located gene DLL1 . Larger deletions that include QKI (> 7.1 Mb) lead to a more severe phenotype that includes additional clinical characteristics. Conclusions Terminal 6q deletions cause a common but highly variable phenotype. Most clinical characteristics can be linked to the smallest terminal 6q deletions that include the gene DLL1 (> 500 kb). Based on our findings, we provide recommendations for clinical follow-up and surveillance of individuals with terminal 6q deletions.

Information on the health‐related consequences of rare chromosome disorders is often limited, posing challenges for both patients and their families. The Chromosome 6 Project aims to bridge this knowledge gap for structural aberrations involving chromosome 6 by providing parents of affected children with information on the expected phenotypes of their child. To achieve this, detailed phenotype and genotype data are collected directly from parents worldwide and supplemented with data from literature reports, resulting thus far in a dataset of over 500 individuals. This comprehensive data pool was used to develop Del2Phen, a software tool introduced in this paper that generates aberration‐specific phenotype information for chromosome disorders. Del2Phen identifies individuals with a deletion or duplication similar to that of a new patient (index) and produces a clinical description for the index based on phenotypic features observed in these genotypically similar individuals. Genotypic similarity is determined using existing knowledge on the haploinsufficiency effect of genes and established gene–phenotype relationships. The optimal genotypic similarity parameters for chromosome 6 deletions were evaluated, which led to thorough and reliable clinical descriptions based on sufficiently large groups of individuals with highly similar deletions. Although currently optimised for chromosome 6 deletions, Del2Phen can also be applied to deletions involving other chromosomes and is easily adapted for use on duplications, given sufficient data are available. Del2Phen can already be used to expedite data analysis for chromosome disorders, thus aiding healthcare professionals in delivering appropriate clinical care. Lastly, this tool will be integrated into an interactive website designed for parents of children with a chromosome 6 aberration, providing essential health information in a timely and accessible manner.

The diagnostic yield of exome and genome sequencing remains low (8–70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases. A genetic diagnosis remains unattainable for many individuals with a rare disease because of incomplete knowledge about the genetic basis of many diseases. Here, the authors present the web-based tool GADO (GeneNetwork Assisted Diagnostic Optimization) that uses public RNA-seq data for prioritization of candidate genes.

CHARGE syndrome is a common cause of congenital anomalies affecting several tissues in a nonrandom fashion. We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array comparative genomic hybridization in two individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals.

Background Terminal 6p deletions are rare, and information on their clinical consequences is scarce, which impedes optimal management and follow-up by clinicians. The parent-driven Chromosome 6 Project collaborates with families of affected children worldwide to better understand the clinical effects of chromosome 6 aberrations and to support clinical guidance. A microarray report is required for participation, and detailed phenotype information is collected directly from parents through a multilingual web-based questionnaire. Information collected from parents is then combined with case data from literature reports. Here, we present our findings on 13 newly identified patients and 46 literature cases with genotypically well-characterised terminal and subterminal 6p deletions. We provide phenotype descriptions for both the whole group and for subgroups based on deletion size and HI gene content. Results The total group shared a common phenotype characterised by ocular anterior segment dysgenesis, vision problems, brain malformations, congenital defects of the cardiac septa and valves, mild to moderate hearing impairment, eye movement abnormalities, hypotonia, mild developmental delay and dysmorphic features. These characteristics were observed in all subgroups where FOXC1 was included in the deletion, confirming a dominant role for this gene. Additional characteristics were seen in individuals with terminal deletions exceeding 4.02 Mb, namely complex heart defects, corpus callosum abnormalities, kidney abnormalities and orofacial clefting. Some of these additional features may be related to the loss of other genes in the terminal 6p region, such as RREB1 for the cardiac phenotypes and TUBB2A and TUBB2B for the cerebral phenotypes. In the newly identified patients, we observed previously unreported features including gastrointestinal problems, neurological abnormalities, balance problems and sleep disturbances. Conclusions We present an overview of the phenotypic characteristics observed in terminal and subterminal 6p deletions. This reveals a common phenotype that can be highly attributable to haploinsufficiency of FOXC1 , with a possible additional effect of other genes in the 6p25 region. We also delineate the developmental abilities of affected individuals and report on previously unrecognised features, showing the added benefit of collecting information directly from parents. Based on our overview, we provide recommendations for clinical surveillance to support clinicians, patients and families.

Proximal 6q (6q11-q15) deletions are extremely rare and little is known about their phenotypic consequences. Since parents and caregivers now use social media to seek information on rare disorders, the Chromosome 6 Project has successfully collaborated with a Facebook group to collect data on individuals worldwide. Here we describe a cohort of 20 newly identified individuals and 25 literature cases with a proximal 6q deletion. Microarray results and phenotype data were reported directly by parents via a multilingual online questionnaire. This led to phenotype descriptions for five subregions of proximal 6q deletions; comparing the subgroups revealed that 6q11q14.1 deletions presented less severe clinical characteristics than 6q14.2q15 deletions. Gastroesophageal reflux, tracheo/laryngo/bronchomalacia, congenital heart defects, cerebral defects, seizures, and vision and respiratory problems were predominant in those with 6q14.2q15 deletions. Problems related to connective tissue (hypermobility, hernias and foot deformities) were predominantly seen in deletions including the COL12A1 gene (6q13). Congenital heart defects could be linked to deletions of MAP3K7 (6q15) or TBX18 (6q14.3). We further discuss the role of ten genes known or assumed to be related to developmental delay and/or autism (BAI3, RIMS1, KCNQ5, HTR1B, PHIP, SYNCRIP, HTR1E, ZNF292, AKIRIN2 and EPHA7). The most influential gene on the neurodevelopmental phenotype seems to be SYNCRIP (6q14.3), while deletions that include more than two of these genes led to more severe developmental delay. We demonstrate that approaching individuals via social media and collecting data directly from parents is a successful strategy, resulting in better information to counsel families.

Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

Heterozygous loss of function mutations in CHD7 (chromodomain helicase DNA-binding protein 7) lead to CHARGE syndrome, a complex developmental disorder affecting craniofacial structures, cranial nerves and several organ systems. Recently, it was demonstrated that CHD7 is essential for the formation of multipotent migratory neural crest cells, which migrate from the neural tube to many regions of the embryo, where they differentiate into various tissues including craniofacial and heart structures. So far, only few CHD7 target genes involved in neural crest cell development have been identified and the role of CHD7 in neural crest cell guidance and the regulation of mesenchymal-epithelial transition are unknown. Therefore, we undertook a genome-wide microarray expression analysis on wild-type and CHD7 deficient (Chd7 Whi/ + and Chd7 Whi/Whi ) mouse embryos at day 9.5, a time point of neural crest cell migration. We identified 98 differentially expressed genes between wild-type and Chd7 Whi/Whi embryos. Interestingly, many misregulated genes are involved in neural crest cell and axon guidance such as semaphorins and ephrin receptors. By performing knockdown experiments for Chd7 in Xenopus laevis embryos, we found abnormalities in the expression pattern of Sema3a, a protein involved in the pathogenesis of Kallmann syndrome, in vivo. In addition, we detected non-synonymous SEMA3A variations in 3 out of 45 CHD7-negative CHARGE patients. In summary, we discovered for the first time that Chd7 regulates genes involved in neural crest cell guidance, demonstrating a new aspect in the pathogenesis of CHARGE syndrome. Furthermore, we showed for Sema3a a conserved regulatory mechanism across different species, highlighting its significance during development. Although we postulated that the non-synonymous SEMA3A variants which we found in CHD7-negative CHARGE patients alone are not sufficient to produce the phenotype, we suggest an important modifier role for SEMA3A in the pathogenesis of this multiple malformation syndrome.

Background Even with the introduction of new genetic techniques that enable accurate genomic characterization, knowledge about the phenotypic spectrum of rare chromosomal disorders is still limited, both in literature and existing databases. Yet this clinical information is of utmost importance for health professionals and the parents of children with rare diseases. Since existing databases are often hampered by the limited time and willingness of health professionals to input new data, we collected phenotype data directly from parents of children with a chromosome 6 disorder. These parents were reached via social media, and the information was collected via the online Chromosome 6 Questionnaire, which includes 115 main questions on congenital abnormalities, medical problems, behaviour, growth and development. Methods Here, we assess data consistency by comparing parent-reported phenotypes to phenotypes based on copies of medical files for the same individual (n = 20) and data availability by comparing the data available on specific characteristics reported by parents (n = 34) to data available in existing literature (n = 39). Results The reported answers to the main questions on phenotype characteristics were 85–95% consistent, and the consistency of answers to subsequent more detailed questions was 77–96%. For all but two main questions, significantly more data was collected from parents via the Chromosome 6 Questionnaire than was currently available in literature. For the topics developmental delay and brain abnormalities, no significant difference in the amount of available data was found. The only feature for which significantly more data was available in literature was a sub-question on the type of brain abnormality present. Conclusion This is the first study to compare phenotype data collected directly from parents to data extracted from medical files on the same individuals. We found that the data was highly consistent, and phenotype data collected via the online Chromosome 6 Questionnaire resulted in more available information on most clinical characteristics when compared to phenotypes reported in literature reports thus far. We encourage active patient participation in rare disease research and have shown that parent-reported phenotypes are reliable and contribute to our knowledge of the phenotypic spectrum of rare chromosomal disorders.