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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 The KCNH1 gene (OMIM #603,305) encodes a voltage-gated potassium channel primarily found in the central nervous system. Recent discoveries have linked pathogenic variations in this gene to Temple-Baraitser syndrome (TMBTS, OMIM #611,816) and Zimmermann-Laband syndrome (ZLS, OMIM #135,500). A common manifestation of these syndromes is gingival fibromatosis, which may partially or completely cover tooth crowns, leading in some cases to functional and aesthetic problems, as well as delayed tooth eruption. Case presentation A four-year-old boy and his parents first consulted for delayed primary molars eruption. Shortly after birth, he was diagnosed with a developmental encephalopathy caused by a de novo pathogenic variant in KCNH1 . Treatment The first step of oral treatment consisted of myofunctional and speech/language therapy to stimulate biting and chewing. It also helped with the rehabilitation of proper tongue function. This was followed by a gingivoplasty to expose the submerged teeth. We propose a clinical approach to optimize disease management. This aims to minimize complications associated with this rare disorder. Conclusion This case illustrates the need for appropriate and early gingivoplasty to prevent teeth impaction and restore dental function. Additionally, it explores potential complications and provides grounds for a comprehensive protocol for managing gingival fibromatosis for patients with KCNH1 variant.

Background SATB2-associated syndrome (SAS) results from various mutations of the SATB2 gene and associates a neurodevelopmental disorder including major speech delay, intellectual disability, and behavioral problems with dental anomalies, sometimes a cleft palate, risk of osteoporosis, and facial dysmorphism. The principal objective of this study was to describe the oral phenotype of young children with SATB2-associated syndrome, especially in terms of orofacial malformation of Robin Sequence (RS) spectrum (bifid uvula, cleft palate, or RS, dental malformation, feeding and communication, with data from a national cohort. The secondary objective was to determine whether feeding and communication disorders were more severe when associated with an orofacial malformation of RS spectrum. Methods We conducted a retrospective cross-sectional study among the largest possible cohort of patients with a mutation of the SATB2 gene in France. A questionnaire completed by the referring physicians and by telephone with parents enabled us to collect the following clinical information: (1) orofacial morphology, feeding difficulties, and pharyngeal functioning from birth to 3 years, (2) communication and language from 0 to 6 years, (3) speech development at the last examination. Results The study included 40 patients. Early and persistent feeding difficulties were found in 55% of the children. Communication was abnormal from the first months of life, with poor babbling in 85% of them. A major language delay was described in all patients; 65% had a vocabulary of 10 words or less. An anomaly of RS spectrum was found in half the cases, and dental malformations were described in 90%. Feeding difficulties and language delay were greater in the group with one or more orofacial malformations than the group with none. Conclusion This study confirmed the severity of oral involvement, affecting feeding and speech simultaneously, in individuals with SAS. It raises the question of why the oral phenotype involving feeding and speech is more severe in the presence of cleft palate or RS. We recommend close monitoring of prelanguage communication in infants with apparently isolated cleft palate or RS and the search for SATB2 impairment when a cleft palate or RS is found, especially in the prenatal period.

Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual—a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with ‘classical’, clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype–phenotype association is fundamental to accurate prognostication for families and caregivers.

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt–Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.

Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by brittle bones. Though genetic mutations in COL1A1 and COL1A2 account for approximately 85–90% of OI cases, there are now more than twenty genes described, responsible for rare forms of OI. Treatment is based on the use of bisphosphonates and though it is well established that they increase lumbar spine (LS) bone mineral density (BMD), the clinical impact on fracture reduction is still debated.In this study, we investigated the clinical characteristics of 38 patients with a bone fragility disorder that had variants in non-COL1A1/COL1A2 genes in order to study genotype-phenotype correlations, as the natural history of these rare forms is still not well known. We then studied the usefulness of bisphosphonate treatment by evaluating the effects on LS BMD, annual non-vertebral fracture rate, bone turnover markers and height. This study enabled us to better define the natural history of patients with non-COL1 pathogenic variants. Patients with CRTAP and TMEM38B variants consistently had a prenatal presentation with a short (<3rd p) and bowed femur. Importantly, this prenatal involvement does not predict the postnatal severity of the disease. Regarding treatment by bisphosphonates, all patients showed a significant increase in LS BMD while treated and this increase was dependent on the dose received. The increase in LS BMD also translated in a reduction of fracture rate during treatment. Finally, our study showed that the earlier bisphosphonates are initiated, the greater the fracture rate is reduced.

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.

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants. Discovering disease genes on the X chromosome can be particularly challenging. Here, the authors use features of known disease genes and machine learning to predict genes that remain to be associated with disorders on this chromosome.

Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype–genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype–genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.

Purpose We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10 . Methods We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF. Results Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling. Conclusion Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.