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BackgroundClubfoot, presenting as a rigid inward and downward turning of the foot, is one of the most common congenital musculoskeletal anomalies. The aetiology of clubfoot is poorly understood and variants in known clubfoot disease genes account for only a small portion of the heritability.MethodsExome sequence data were generated from 1190 non-syndromic clubfoot cases and their family members from multiple ethnicities. Ultra-rare variant burden analysis was performed comparing 857 unrelated clubfoot cases with European ancestry with two independent ethnicity-matched control groups (1043 in-house and 56 885 gnomAD controls). Additional variants in prioritised genes were identified in a larger cohort, including probands with non-European ancestry. Segregation analysis was performed in multiplex families when available.ResultsRare variants in 29 genes were enriched in clubfoot cases, including PITX1 (a known clubfoot disease gene), HOXD12, COL12A1, COL9A3 and LMX1B. In addition, rare variants in posterior HOX genes (HOX9–13) were enriched overall in clubfoot cases. In total, variants in these genes were present in 8.4% (100/1190) of clubfoot cases with both European and non-European ancestry. Among these, 3 are de novo and 22 show variable penetrance, including 4 HOXD12 variants that segregate with clubfoot.ConclusionWe report HOXD12 as a novel clubfoot disease gene and demonstrate a phenotypic expansion of known disease genes (myopathy gene COL12A1, Ehlers-Danlos syndrome gene COL9A3 and nail-patella syndrome gene LMX1B) to include isolated clubfoot.

Background Also known as clubfoot, idiopathic congenital talipes equinovarus (ICTEV) is the most common pediatric deformity and occurs in 1 in every 1000 live births. Even though it has been widely researched, the etiology of ICTEV remains poorly understood and is often described as being based on a multifactorial genesis. Genetic and environmental factors seem to have a major role in the development of this disease. Thus, the aim of this review is to analyze the available literature to document the current evidence on ICTEV etiology. Methods The literature on ICTEV etiology was systematically reviewed using the following inclusion criteria: studies of any level of evidence, reporting clinical or preclinical results, published in the last 20 years (1998–2018), and dealing with the etiology of ICTEV. Results A total of 48 articles were included. ICTEV etiology is still controversial. Several hypotheses have been researched, but none of them are decisive. Emerging evidence suggests a role of several pathways and gene families associated with limb development (HOX family; PITX1-TBX4), the apoptotic pathway (caspases), and muscle contractile protein (troponin and tropomyosin), but a major candidate gene has still not been identified. Strong recent evidence emerging from twin studies confirmed major roles of genetics and the environment in the disease pathogenesis. Conclusions The available literature on the etiology of ICTEV presents major limitations in terms of great heterogeneity and a lack of high-profile studies. Although many studies focus on the genetic background of the disease, there is lack of consensus on one or multiple targets. Genetics and smoking seem to be strongly associated with ICTEV etiology, but more studies are needed to understand the complex and multifactorial genesis of this common congenital lower-limb disease.

The aim of this article is to publish a literature review and report on two new cases of Gordon syndrome (GS), a rare syndrome documented to have an autosomal dominant inheritance pattern or to occur sporadically; it is characterized by camptodactyly, cleft palate, and talipes equinovarus. We report two exceptional cases of GS where both patients were also diagnosed with congenital myopathy, and one developed malignant hyperthermia. These are the first two cases reported where patients were diagnosed with both GS and congenital myopathy or where GS is associated with malignant hyperthermia.

Disorders that result from de-arrangement of growth, development and/or differentiation of the appendages (limbs and digit) are collectively called as inherited abnormalities of human appendicular skeleton. The bones of appendicular skeleton have central role in locomotion and movement. The different types of appendicular skeletal abnormalities are well described in the report of “Nosology and Classification of Genetic skeletal disorders: 2019 Revision”. In the current article, we intend to present the embryology, developmental pathways, disorders and the molecular genetics of the appendicular skeletal malformations. We mainly focused on the polydactyly, syndactyly, brachydactyly, split-hand–foot malformation and clubfoot disorders. To our knowledge, only nine genes of polydactyly, five genes of split-hand–foot malformation, nine genes for syndactyly, eight genes for brachydactyly and only single gene for clubfoot have been identified to be involved in disease pathophysiology. The current molecular genetic data will help life sciences researchers working on the rare skeletal disorders. Moreover, the aim of present systematic review is to gather the published knowledge on molecular genetics of appendicular skeleton, which would help in genetic counseling and molecular diagnosis.

Introduction The aim of this study is to evaluate the benefit of cytogenetic testing by amniocentesis after an ultrasound diagnosis of isolated bilateral talipes equinovarus. Material and methods This multicenter observational retrospective study includes all prenatally diagnosed cases of isolated bilateral talipes equinovarus in five fetal medicine centers from 2012 through 2021. Ultrasound data, amniocentesis results, biochemical analyses of amniotic fluid and parental blood samples to test neuromuscular diseases, pregnancy outcomes, and postnatal outcomes were collected for each patient. Results In all, 214 fetuses with isolated bilateral talipes equinovarus were analyzed. A first‐degree family history of talipes equinovarus existed in 9.8% (21/214) of our cohort. Amniocentesis was proposed to 86.0% (184/214) and performed in 70.1% (129/184) of cases. Of the 184 karyotypes performed, two (1.6%) were abnormal (one trisomy 21 and one triple X syndrome). Of the 103 microarrays performed, two (1.9%) revealed a pathogenic copy number variation (one with a de novo 18p deletion and one with a de novo 22q11.2 deletion) (DiGeorge syndrome). Neuromuscular diseases (spinal muscular amyotrophy, myasthenia gravis, and Steinert disease) were tested for in 56 fetuses (27.6%); all were negative. Overall, 97.6% (165/169) of fetuses were live‐born, and the diagnosis of isolated bilateral talipes equinovarus was confirmed for 98.6% (139/141). Three medical terminations of pregnancy were performed (for the fetuses diagnosed with Down syndrome, DiGeorge syndrome, and the 18p deletion). Telephone calls (at a mean follow‐up age of 4.5 years) were made to all parents to collect medium‐term and long‐term follow‐up information, and 70 (33.0%) families were successfully contacted. Two reported a rare genetic disease diagnosed postnatally (one primary microcephaly and one infantile glycine encephalopathy). Parents did not report any noticeably abnormal psychomotor development among the other children during this data collection. Conclusions Despite the low rate of pathogenic chromosomal abnormalities diagnosed prenatally after this ultrasound diagnosis, the risk of chromosomal aberration exceeds the risks of amniocentesis. These data may be helpful in prenatal counseling situations. This study confirms the need to offer amniocentesis for isolated bilateral talipes equinovarus and suggests that molecular genetic tests such as gene panels or whole exome sequencing may increase the diagnostic yield in fetuses with this condition.

Background Congenital talipes equinovarus (CTEV) is a prevalent pediatric deformity with a multifactorial etiology. The objective of this meta-analysis was to explore the association between genetic variations in COL9A1 and the susceptibility to CTEV. Methods A comprehensive analysis of pertinent literature released before November 15, 2023, in electronic bibliographic databases was carried out. The importance of the connection was clarified through odds ratios (ORs) with 95% confidence intervals (CIs), utilizing random or fixed-effects models depending on study heterogeneity. Statistical analysis was executed using Comprehensive Meta-Analysis software (Version 4.0). Results A total of eight case-control studies involving 833 CTEV patients and 1280 healthy individuals were included in the analysis. Among these, four studies investigated the rs1135056 variant, encompassing 432 CTEV cases and 603 controls; two studies examined the rs35470562 variant, with 189 CTEV cases and 378 controls; and two studies explored the rs592121 variant, including 212 CTEV cases and 299 controls. The results revealed a significant association between the rs1135056 and rs35470562 polymorphisms in the COL9A1 gene, suggesting an increased risk of CTEV in the overall population. Conversely, no such association was found for the rs592121 variant. Conclusion Our findings reveal a substantial association between the genetic variants COL9A1 rs1135056 and rs35470562 and susceptibility to CTEV. Conversely, the variant rs592121 did not exhibit any corresponding link. However, the limitations imposed by the small study population have compromised the statistical reliability and generalizability of the results.

Clubfoot (talipes equinovarus) is a congenital malformation affecting muscles, bones, connective tissue and vascular or neurological structures in limbs. It has a complex aetiology, both genetic and environmental. To date, the most important findings in clubfoot genetics involve PITX1 variants, which were linked to clubfoot phenotype in mice and humans. Additionally, copy number variations encompassing TBX4 or single nucleotide variants in HOXC11, the molecular targets of the PITX1 transcription factor, were linked to the clubfoot phenotype. In general, genes of cytoskeleton and muscle contractile apparatus, as well as components of the extracellular matrix and connective tissue, are frequently linked with clubfoot aetiology. Last but not least, an equally important element, that brings us closer to a better understanding of the clubfoot genotype/phenotype correlation, are studies on the two known animal models of clubfoot—the pma or EphA4 mice. This review will summarise the current state of knowledge of the molecular basis of this congenital malformation.

BackgroundDeletions of the HOXC gene cluster result in variable phenotypes in mice, but have been rarely described in humans.ObjectiveTo report chromosome 12q13.13 microdeletions ranging from 13 to 175 kb and involving the 5′ HOXC genes in four families, segregating congenital lower limb malformations, including clubfoot, vertical talus and hip dysplasia.MethodsProbands (N=253) with clubfoot or vertical talus were screened for point mutations and copy number variants using multiplexed direct genomic selection, a pooled BAC targeted capture approach. SNP genotyping included 1178 probands with clubfoot or vertical talus and 1775 controls.ResultsThe microdeletions share a minimal non-coding region overlap upstream of HOXC13, with variable phenotypes depending upon HOXC13, HOXC12 or the HOTAIR lncRNA inclusion. SNP analysis revealed HOXC11 p.Ser191Phe segregating with clubfoot in a small family and enrichment of HOXC12 p.Asn176Lys in patients with clubfoot or vertical talus (rs189468720, p=0.0057, OR=3.8). Defects in limb morphogenesis include shortened and overlapping toes, as well as peroneus muscle hypoplasia. Finally, HOXC and HOXD gene expression is reduced in fibroblasts from a patient with a 5′ HOXC deletion, consistent with previous studies demonstrating that dosage of lncRNAs alters expression of HOXD genes in trans.ConclusionsBecause HOXD10 has been implicated in the aetiology of congenital vertical talus, variation in its expression may contribute to the lower limb phenotypes occurring with 5′ HOXC microdeletions. Identification of 5′ HOXC microdeletions highlights the importance of transcriptional regulators in the aetiology of severe lower limb malformations and will improve their diagnosis and management.

Gordon syndrome is a rare inherited monogenic form of hypertension, which is associated with hyperkalaemia and metabolic acidosis. Since the recognition of this predominantly autosomal dominant condition in the 1960s, the study of families with Gordon syndrome has revealed four genes WNK1, WNK4, KLHL3, and CUL3 to be implicated in its pathogenesis after a phenotype–genotype correlation was realised. The encoded proteins Kelch-like 3 and Cullin 3 interact to form a ring-like complex to ubiquitinate WNK-kinase 4, which, in normal circumstances, interacts with the sodium chloride co-symporter (NCC), the epithelial sodium channel (ENaC), and the renal outer medullary potassium channel (ROMK) in an inhibitory manner to maintain normokalaemia and normotension. WNK-kinase 1 has an inhibitory action on WNK-kinase 4. Mutations in WNK1, WNK4, KLHL3, and CUL3 all result in the accumulation of WNK-kinase 4 and subsequent hypertension, hyperkalaemia, and metabolic acidosis. This review explains the clinical aspects, disease mechanisms, and molecular genetics of Gordon syndrome.

Background Multiple molecular diagnoses (MMD) involve distinct or overlapping phenotypes. They are not so rare in the field of congenital anomalies, given an overall 3.5%–8% rate. Mainly, MMD imply distinct genotypes. Exceptionally, genotypes are linked, involving a causal CNV by itself, facing a SNV for a recessive disorder resulting in a dual diagnosis. Methods An unrelated couple was referred at 21 + 3 weeks of gestation for talipes equinovarus, cerebellar hypoplasia, clenched fists, elevated hemidiaphragm, and micrognathia. Chromosomal microarray and exome sequencing analyses were performed. Results Both identified a pathogenic de novo 22q11.21 deletion (22q11.2del). Fetal autopsy revealed additional features (postaxial polydactyly, facial features, and abnormal lung lobulation), atypical for 22q11.2del syndrome. At the clinician's request, exome sequencing reanalysis identified a paternally inherited SCARF2 variant, in trans to the 22q11.2del causing autosomal recessive Van den Ende–Gupta syndrome. This dual diagnosis explains the entire fetus phenotype. Discussion This is a novel case of dual diagnosis, first prenatal and second case of this ultrarare association. It reflects the crucial role of precise phenotypic description, combined with the importance of considering dual diagnosis in case of atypical clinical presentation. Finally, prenatal phenotypes remain a challenge given the paucity of available known prenatal data for most rare diseases. Trial Registration ClinicalTrial.gov ID: NCT05182242 We report here the first prenatal dual molecular diagnosis, involving 22q11.2 deletion and Van den Ende‐Gupta symdromes. A de novo 22q11.2 deletion was initially detected both by chromosal microarray and exome sequencing. Given atypical additional clinical signs at fetal autopsy, reanalysis of exome sequencing revealed a pathogenic SCARF2 variant in trans, paternally inherited, consistent with autosomal recessive Van den Ende‐Gupta syndrome. The combined findings fully explain the phenotype, underscoring the importance of considering dual diagnoses in case of atypical clinical presentation.