Case Report: Prenatal Diagnosis of Postaxial Polydactyly With Bi-Allelic Variants in Smoothened (SMO).
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ABSTRACT:
SUBMITTER: Fan L
PROVIDER: S-EPMC9257524 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A?>?T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.
| S-EPMC6724712 | biostudies-literature
Project description:Pallister-Hall syndrome, typically caused by germline or de novo variants within the GLI3 gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a few similar cases have been described with bi-allelic SMO variants. We describe two siblings born to non-consanguineous unaffected parents presenting with hypothalamic hamartoma, post-axial polydactyly, microcephaly amongst other developmental anomalies. Previous clinical diagnostic exome analysis had excluded a pathogenic variant in GLI3. We performed exome sequencing re-analysis and identified bi-allelic SMO variants including a missense and synonymous variant in both affected siblings. We functionally characterised this synonymous variant showing it induces exon 8 skipping within the SMO transcript. Our results confirm bi-allelic SMO variants as an uncommon cause of Pallister-Hall syndrome and describe a novel exon-skipping mechanism, expanding the molecular architecture of this new clinico-molecular disorder.
| S-EPMC8904774 | biostudies-literature
Project description:Postaxial polydactyly (PAP) is a common abnormality characterized by extra digits on hands and/or feet. To date, sequence variants in seven genes have been identified in non-syndromic PAP. In the present study, a fetus manifesting non-syndromic postaxial polydactyly type A (PAPA) was found by fetal ultrasonography. To better evaluate fetal prognosis, SNP array analysis and trio whole-exome sequencing (trio-WES) were performed to identify the underlying etiology. Although SNP array analysis revealed no abnormality, trio-WES identified compound heterozygous splice site variants in KIAA0825, c.-1-2A>T and c.2247-2A>G in intron 2 and intron 12, respectively. These two splice site variants were absent in control databases and were predicted to influence splicing by in silico analysis. To confirm the potential pathogenicity of the variants, in vitro splicing assays using minigene and RNA from peripheral leukocytes of the heterozygous parents were conducted. Minigene and RT-PCR assays demonstrated that the c.-1-2A>T variant led to the loss of the initiation codon, and the c.2247-2A>G variant mainly resulted in exon 13 skipping. Prenatal WES and subsequent functional studies are important approaches for defining the genetic etiology of fetuses with PAPA and are also essential for accurate genetic counseling and decision making. Taken together, this study expands the spectrum of KIAA0825 variations in PAPA patients and increases the knowledge of the molecular consequences of KIAA0825 splice site variants.
| S-EPMC9316509 | biostudies-literature
Project description:BackgroundPostaxial polydactyly (PAP) is one of the commonest congenital malformations and usually is associated to several syndromes. There is no primary investigational strategy for PAP cases with single gene disorder in literature. PAP cases with single gene disorder can be classified according to common pathways and molecular basis. Molecular classification may help in diagnostic approach.Materials and methodsAll single gene disorders associated with PAP reported on PubMed and OMIM are analyzed and classified according to molecular basis.ResultsMajority of genes related to cilia structure and functions are associated with PAP, so we classified them as ciliopathies and non-ciliopathies groups. Genes related to Shh-Gli3 pathway was the commonest group in non-ciliopathies.ConclusionGenes related to cilia are most commonly related to PAP due to their indirect relationship to Shh-Gli3 signaling pathway. Initially, PAP may be the only clinical finding with ciliopathies so those cases need follow up. Proper diagnosis is helpful for management and genetic counseling. Molecular approach may help to define pleiotropy.
| S-EPMC4324078 | biostudies-literature
Project description:Postaxial polydactyly (PAP) is characterized by counterproductive 5th digit (pinky finger) duplication on hands and/or feet which often leads to functional complications. To date, at least 11 genes involved in causing various types of nonsyndromic polydactylies have been reported. In the present study, a consanguineous family of Sindhi origin with a segregating nonsyndromic form of PAP in an autosomal recessive manner was clinically and genetically evaluated. Genotyping, using polymorphic microsatellite markers, established linkage in the family on chromosome 5q15 harboring the KIAA0825 gene (MIM 617266). Sequence analysis of the gene revealed a novel frameshift variant leading to a premature stop codon [c.143delG, p.(Cys48Serfs*28)]. This is only the 4th novel variant in the KIAA0825 gene that leads to PAP type A10 (PAPA10) (MIM 618498). Identification of variants in the PAP causative gene will support the diagnosis of patients with limb malformations in the Pakistani population.
| S-EPMC7983616 | biostudies-literature
Project description:Background: There have been many reports on the classification and treatment of postaxial polydactyly of the foot. However, despite its being a common congenital anomaly, there is no universal notation about its morphology. Methods: We performed an analysis of 65 postaxial polydactyly cases from 2004 to 2021. Judgment criteria for deciding the surgical procedure were selected, and the points required for notation were decided. Based on them, we devised a new notation. Results: The necessary points required for notation were decided based on the following criteria: (1) the presence and level of syndactyly, (2) bifurcation level of the phalanges, (3) the presence of other deformities, and (4) predominant toes. We came up with a new notation and description method. Different types of syndactyly were represented using a horizontal bar, and predominant toes were represented using equality or inequality symbols. The bifurcation level of the phalanges and accessory deformities were additionally recorded (eg, 4—5>—6, Middle, 5,6: External rotation). From this notation, it is obvious which toe should be resected. Furthermore, syndactyly, accessory deformities, and the condition of the phalanges are also easily understood. Conclusions: Our new notation for postaxial polydactyly consists of some related symbols that are each provided a meaning. This system is simple, especially for easily understanding the morphology, and ideal for daily medical use. We conclude that it could become a universal notation method for cases of postaxial polydactyly of the foot.
| S-EPMC9633084 | biostudies-literature
Project description:BackgroundPostaxial polydactyly is a common congenital foot anomaly. However, the severity of the anomaly varies from simple cases with only soft tissue duplication to complex cases with bone and joint disorders. In our clinical practice, we found a new morphological anomaly of postaxial polydactyly. We encountered several cases of postaxial polydactyly with bone fragments located between the fourth and fifth toes. The bone fragments were independent of the joint cavity. The mechanisms underlying its development remain unknown because it is a novel disorder. In the present study, we investigated the characteristics of the excess bone to formulate an embryological hypothesis.MethodsWe examined the frequency and trends in the occurrence of excess bone using data from photographs and radiographs of these cases. An example of a disorder similar to excess bone is mosaic-like alignment, as reported by Iba et al. We also compared the characteristics of the mosaic-like alignment with those of the excess bone. Based on these data and existing embryological knowledge, we hypothesized the origin of the excess bone.ResultsExcess bone and mosaic-like alignments showed different characteristics. Therefore, both were considered completely different disorders. We hypothesized that excess bone was caused by damage to the interdigital ectoderm immediately before interdigital programmed cell death.ConclusionsWe encountered a new form of postaxial polydactyly. This can be a factor influencing the treatment strategy because it can affect alignment and stability.
| S-EPMC11000771 | biostudies-literature
Project description:Pontocerebellar hypoplasia (PCH) describes a group of rare heterogeneous neurodegenerative diseases with prenatal onset. Here we describe eight children with PCH from four unrelated families harboring the homozygous MINPP1 (NM_004897.4) variants; c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), and c.992 T > G, p.(Ile331Ser). The homozygous p.(Leu27Argfs*39) change is predicted to result in a complete absence of MINPP1. The p.(Arg404*) would likely lead to a nonsense mediated decay, or alternatively, a loss of several secondary structure elements impairing protein folding. The missense p.(Ala284Asp) affects a buried, hydrophobic residue within the globular domain. The introduction of aspartic acid is energetically highly unfavorable and therefore predicted to cause a significant reduction in protein stability. The missense p.(Ile331Ser) affects the tight hydrophobic interactions of the isoleucine by the disruption of the polar side chain of serine, destabilizing the structure of MINPP1. The overlap of the above-mentioned genotypes and phenotypes is highly improbable by chance. MINPP1 is the only enzyme that hydrolyses inositol phosphates in the endoplasmic reticulum lumen and several studies support its role in stress induced apoptosis. The pathomechanism explaining the disease mechanism remains unknown, however several others genes of the inositol phosphatase metabolism (e.g., INPP5K, FIG4, INPP5E, ITPR1) are correlated with phenotypes of neurodevelopmental disorders. Taken together, we present MINPP1 as a novel autosomal recessive pontocerebellar hypoplasia gene.
| S-EPMC7940488 | biostudies-literature
Project description:The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.
| S-EPMC7273534 | biostudies-literature
Project description:PurposeMultiple morphological abnormalities in the sperm flagella (MMAF) comprise a severe phenotype of asthenoteratozoospermia with reduced or absent spermatozoa motility. Whereas dozens of candidate pathogenic genes for MMAF have been identified, the genetic cause in a large proportion of patients is unknown. We attempted to identify novel genetic explanations for MMAF.MethodsWe performed whole-exome sequencing of patients with MMAF to identify pathogenic variants. The phenotypes of spermatozoa in patients carrying DNAH10 variants were investigated using haematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy. The expression and location of DNAH10 and other spermatozoa structure-related proteins were analyzed using immunofluorescence assays.ResultsWe found one homozygous frameshift DNAH10 variant (NM_207437: c.2514delG:p.L839*) and one compound heterozygous DNAH10 variant (NM_207437: c.10820 T > C:p.M3607T; c.12692C > T:p.T4231I) in two patients with MMAF. These variants were absent or rare in the general population. Haematoxylin and eosin staining and scanning electron microscopy revealed the significant disruption of sperm flagella in the patients. In addition, ultrastructural analysis by transmission electron microscopy showed significant inner dynein arm (IDA) deficiency in sperm flagella. Using immunofluorescence assays, we found a significant reduction in IDA-related proteins including DNAH10 and DNAH1.ConclusionsWe identified putative novel pathogenic variants in DNAH10 for MMAF, which might advance the genetic diagnosis and clinical genetic counselling for male infertility.
| S-EPMC8866613 | biostudies-literature