-
Nature Feb 2024Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied...
Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.
Topics: Humans; Enhancer Elements, Genetic; Extremities; Gain of Function Mutation; Homeodomain Proteins; Interferon Regulatory Factors; Organ Specificity; Penetrance; Phenotype; Polydactyly; Polymorphism, Single Nucleotide; Protein Binding; Proto-Oncogene Proteins c-ets; Transcription Factor AP-1
PubMed: 38233525
DOI: 10.1038/s41586-023-06922-8 -
Journal of Feline Medicine and Surgery Dec 2020Polydactyly has been described in two breeds of domestic cats (Maine Coon and Pixie Bob) and in some outbred domestic cats (eg, Hemingway cats). In most cases, feline...
OBJECTIVES
Polydactyly has been described in two breeds of domestic cats (Maine Coon and Pixie Bob) and in some outbred domestic cats (eg, Hemingway cats). In most cases, feline polydactyly is a non-syndromic preaxial polydactyly. Three variants located in a regulatory sequence involved in limb development, named ZRS (zone of polarising activity regulatory sequence), have been identified to be responsible for feline polydactyly. These variants have been found in outbred domestic cats in the UK ( and variants) and in Hemingway cats in the USA ( variant). The aim of this study was to characterise the genetic features of polydactyly in Maine Coon cats.
METHODS
Genotyping assay was used to identify the variant(s) segregating in a cohort of 75 polydactyl and non-polydactyl Maine Coon cats from different breeding lines from Europe, Canada and the USA. The authors performed a segregation analysis to identify the inheritance pattern of polydactyly in this cohort and analysed the population structure.
RESULTS
The allele was identified in a subset of polydactyl cats. Sequencing of two regulatory sequences involved in limb development did not reveal any other variant in polydactyl cats lacking the allele. Additionally, genotype-phenotype and segregation analyses revealed the peculiar inheritance pattern of polydactyly in Maine Coon cats. The population structure analysis demonstrated a genetic distinction between and -free polydactyl cats.
CONCLUSIONS AND RELEVANCE
Polydactyly in Maine Coon cats is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity, and this trait is characterised by genetic heterogeneity in the Maine Coon breed. Maine Coon breeders should be aware of this situation and adapt their breeding practices accordingly.
Topics: Animals; Canada; Cats; Europe; Female; Genetic Heterogeneity; Male; Polydactyly; United States
PubMed: 32067556
DOI: 10.1177/1098612X20905061 -
Cells Jul 2021Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary... (Review)
Review
Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.
Topics: Animals; Axonemal Dyneins; Cilia; Ciliopathies; Cytoplasmic Dyneins; Humans; Kartagener Syndrome; Polymorphism, Genetic; Short Rib-Polydactyly Syndrome
PubMed: 34440654
DOI: 10.3390/cells10081885 -
European Journal of Pediatrics Sep 2012Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment.... (Review)
Review
Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment. Ciliary dysfunction has been shown to underlie a broad range of overlapping, clinically and genetically heterogeneous phenotypes, collectively termed ciliopathies. Literally, all organs can be affected. Frequent cilia-related manifestations are (poly)cystic kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous system, occurring either isolated or as part of syndromes. Characterization of ciliopathies and the decisive role of primary cilia in signal transduction and cell division provides novel insights into tumorigenesis, mental retardation, and other common causes of morbidity and mortality, including diabetes mellitus and obesity. New technologies ("Next generation sequencing/NGS") have considerably improved genetic research and diagnostics by allowing simultaneous investigation of all disease genes at reduced costs and lower turn-around times. This is undoubtedly a result of the dynamic development in the field of human genetics and deserves increased attention in genetic counselling and the management of affected families.
Topics: Bardet-Biedl Syndrome; Ciliary Motility Disorders; Genetic Testing; Humans; Kidney Diseases, Cystic; Short Rib-Polydactyly Syndrome
PubMed: 21898032
DOI: 10.1007/s00431-011-1553-z -
Revista Paulista de Pediatria : Orgao... 2023To evaluate radiological (gestational and perinatal) and neonatal signs of patients with Patau syndrome and semilobar holoprosencephaly, as well as to report the...
OBJECTIVE
To evaluate radiological (gestational and perinatal) and neonatal signs of patients with Patau syndrome and semilobar holoprosencephaly, as well as to report the association of both pathologies.
CASE DESCRIPTION
This case report is about a female infant, born at term with trisomy of the chromosome 13 and semilobar holoprosencephaly, with thalamic fusion and a single cerebral ventricle, in addition to several other changes that worsened the patient's prognosis.
COMMENTS
Chromosome 13 trisomy is a genetic alteration that leads to the symptoms that determines Patau syndrome. In this syndrome, cardiovascular, urogenital, central nervous system, facial structure and intellectual impairment are common, in addition to problems in limb formation, such as decreased humerus and femur length, polydactyly, hypotelorism and low ear implantation. It is estimated, however, that holoprosencephaly is present in only 24 to 45% of the patients with trisomy 13.
Topics: Infant, Newborn; Pregnancy; Infant; Humans; Female; Holoprosencephaly; Trisomy 13 Syndrome; Trisomy; Polydactyly; Mutation; Chromosomes, Human, Pair 13
PubMed: 36921175
DOI: 10.1590/1984-0462/2023/41/2022027 -
Journal of Medical Case Reports Apr 2022Bardet-Biedl syndrome is a rare multisystem autosomal recessive disorder that falls under the spectrum of ciliopathy disorders. It is characterized by rod-cone...
BACKGROUND
Bardet-Biedl syndrome is a rare multisystem autosomal recessive disorder that falls under the spectrum of ciliopathy disorders. It is characterized by rod-cone dystrophy, renal malformations, polydactyly, learning difficulties, central obesity, and hypogonadism. Many minor features that are related with Bardet-Biedl syndrome might aid in diagnosis and are crucial in clinical management. Bardet-Biedl syndrome is diagnosed on the basis of clinical signs and symptoms, which can be confirmed by genetic testing. Here we present four cases of Bardet-Biedl syndrome. To our knowledge, these are the first cases of Bardet-Biedl syndrome reported from Sudan.
CASE PRESENTATION
Here, we report four Sudanese patients who presented with a variety of clinical manifestations of Bardet-Biedl syndrome (two males, 50 and 16 years old; two females, 38 and 18 years old). The first two patients presented with features of chronic kidney disease. The third patient had recently been diagnosed with type 1 diabetes and diabetic ketoacidosis. The fourth patient showed signs of retinal dystrophy early on. Case 1: a 38-year-old female presented with vomiting and irritability; the patient was diagnosed with Bardet-Biedl syndrome as she fulfilled six items of the primary features (obesity, retinitis pigmentosa, post-axial polydactyly, renal abnormalities, learning disabilities, and genitourinary malformations), as well as one secondary feature (cardiovascular involvement, that is, left ventricular hypertrophy). Case 2: a 50-year-old male presented with fatigability; the patient was diagnosed with Bardet-Biedl syndrome as he fulfilled four items of the primary features (obesity, retinitis pigmentosa, post-axial polydactyly, and renal abnormalities) in addition to two secondary features (diabetes mellitus and cardiovascular involvement, that is, left ventricular hypertrophy). Case 3: an 18-year-old female presented with polyuria, polydipsia, weight loss, and epigastric pain for 2 days; the patient was diagnosed with Bardet-Biedl syndrome because he had four major features (retinal dystrophy, post-axial polydactyly, obesity, and learning disabilities) in addition to three secondary features (developmental delay, diabetes mellitus, and strabismus). Case 4: a 16-year-old male presented with a blurring of vision; the patient was diagnosed with Bardet-Biedl syndrome as he exhibited four major features (retinal dystrophy, post-axial polydactyly, obesity, and learning disabilities) plus two secondary features (developmental delay and cataract).
CONCLUSION
The scarcity of Bardet-Biedl syndrome necessitates a high index of suspicion to diagnose this syndrome. Increased awareness among physicians is required for the early diagnosis and treatment of Bardet-Biedl syndrome and to avoid complications and mortality.
Topics: Adolescent; Adult; Bardet-Biedl Syndrome; Female; Fingers; Humans; Hypertrophy, Left Ventricular; Kidney; Learning Disabilities; Male; Middle Aged; Obesity; Polydactyly; Retinitis Pigmentosa; Toes; Urogenital Abnormalities
PubMed: 35484558
DOI: 10.1186/s13256-022-03396-6 -
European Journal of Human Genetics :... Apr 2023Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly...
Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.
Topics: Humans; Ciliopathies; Cytoplasmic Dyneins; Ellis-Van Creveld Syndrome; Mutation; Polydactyly
PubMed: 36599940
DOI: 10.1038/s41431-022-01276-7 -
Neurology India 2023
Topics: Child; Humans; Polydactyly; Seizures
PubMed: 37929493
DOI: 10.4103/0028-3886.388066 -
Plastic and Reconstructive Surgery.... Nov 2017Syndactyly and polydactyly-respectively characterized by fused and supernumerary digits-are among the most common congenital limb malformations, with syndactyly...
Syndactyly and polydactyly-respectively characterized by fused and supernumerary digits-are among the most common congenital limb malformations, with syndactyly presenting at an estimated incidence of 1 in 2,000-3,000 live births and polydactyly at a frequency of 1 in approximately 700-1,000 live births. Despite their relatively regular manifestation in the clinic, the etiologies of syndactyly and polydactyly remain poorly understood because of their phenotypic and genetic diversity. Further, even though concrete knowledge of genotypic links has been established for some variants of syndactyly and polydactyly, there appears to be no single comprehensive published summary of all syndromic and nonsyndromic syndactyly and polydactyly presentations, and there is decidedly no resource that maps all syndromic and nonsyndromic syndactylies and polydactylies to their genetic bases. This gap in the literature problematizes comprehensive carrier screening and prenatal diagnosis and complicates novel diagnostic attempts. This review thus attempts to collect all that is known about the genetic bases of syndromic and nonsyndromic syndactylies and polydactylies, as well as to highlight the dactyly manifestations for which no genetic bases are as yet known. Then, having established a summation of existing and missing knowledge, this work briefly outlines the diagnostic techniques that a genetics-reinforced understanding of syndactyly and polydactyly could inform.
PubMed: 29263957
DOI: 10.1097/GOX.0000000000001549 -
The Journal of Hand Surgery, European... Dec 2023Ulnar dimelia is a very rare unilateral congenital upper limb anomaly (CULA) affecting the whole extremity. Treatment remains difficult because of the complexity and... (Review)
Review
Ulnar dimelia is a very rare unilateral congenital upper limb anomaly (CULA) affecting the whole extremity. Treatment remains difficult because of the complexity and multi-level involvement. Twenty-four cases with duplicated ulna, absent radius and polydactyly from seven European centres were reviewed according to a structured list of parameters. At first consultation, median age 8 months (1-178), the shoulder movement was good in 17 patients or poor in six, and the median passive elbow range of motion was 20° (0°-90°). The resting wrist position was flexed in 22/24 patients. Following stretching and splinting, elbow surgery included resection of the lateral proximal ulna in 11 patients and muscle transfers in six to improve passive movement and increase active elbow motion, respectively. Tendon transfers were performed in eight wrists and a pollicization or pseudo-pollicization in 23 patients. Overall, patients demonstrate acceptable function postoperatively. Guidelines for treatment of this severe CULA are presented. IV.
Topics: Humans; Hand Deformities, Congenital; Ulna; Polydactyly; Wrist Joint; Upper Extremity; Radius
PubMed: 37684016
DOI: 10.1177/17531934231196418