A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

2016 ◽  
Vol 149 (3) ◽  
pp. 171-175 ◽  
Author(s):  
Pan-Feng Wu ◽  
Shuai Guo ◽  
Xue-Feng Fan ◽  
Liang-Liang Fan ◽  
Jie-Yuan Jin ◽  
...  
Keyword(s):  
De Novo ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Patient ◽  
Regulatory Sequence ◽  
Preaxial Polydactyly ◽  
Thumb Duplication ◽  
Zone Of Polarizing Activity ◽  
The Right ◽  
Triphalangeal Thumb

Preaxial polydactyly (PPD; OMIM 603596), which is characterized as having supernumerary fingers, is an unusual congenital hand abnormality. Triphalangeal thumb (TPT; OMIM 190600) is identified by an extra phalangeal bone and is often found in association with PPD. When in combination, the disease is referred to as PPD type II (PPD II; OMIM 174500). Previous studies have demonstrated that variations in the zone of polarizing activity regulatory sequence (ZRS; chr7:156,583,796-156,584,569; hg19) region are associated with PPD II. In this study, our patient was diagnosed with PPD II, having bilateral thumb duplication and unilateral TPT (on the right hand). Further investigation of possible causative genes identified a de novo heterozygous ZRS mutation (ZRS 428T>A). This novel mutation was neither found in 200 normal controls nor reported in online databases. Moreover, the bioinformatics program Genomic Evolutionary Rate Profiling (GERP) revealed this site (ZRS428) to be evolutionarily highly conserved, and the 428T>A point mutation was predicted to be deleterious by MutationTaster. In conclusion, the affected individual shows bilateral thumb duplication, but unilateral TPT making this case special. Thus, our findings not only further support the important role of ZRS in limb morphogenesis and expand the spectrum of ZRS mutations, but also emphasize the significance of genetic diagnosis and counseling of families with digit number and identity alterations as well.

A novel mutation in theSHHlong-range regulator (ZRS) is associated with preaxial polydactyly, triphalangeal thumb, and severe radial ray deficiency

2012 ◽  
Vol 158A (10) ◽  
pp. 2610-2615 ◽  
Author(s):  
Mohammad M. Al-Qattan ◽  
Ibrahim Al Abdulkareem ◽  
Yazied Al Haidan ◽  
Mohammed Al Balwi
Keyword(s):  
Novel Mutation ◽  
Preaxial Polydactyly ◽  
Triphalangeal Thumb

A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA)

2016 ◽  
Vol 29 (3) ◽  
Author(s):  
Chen Fang ◽  
Xin Ding ◽  
Yun Huang ◽  
Jian Huang ◽  
Pengjun Zhao ◽  
...  
Keyword(s):  
Birth Weight ◽  
Missense Mutation ◽  
Glutamate Dehydrogenase ◽  
De Novo ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Congenital Hyperinsulinism ◽  
Normal Birth Weight ◽  
Normal Birth

AbstractHyperinsulinism-hyperammonemia (HI/HA) syndrome, often characterized by recurrent symptomatic hypoglycemia and persistent hyperammonemia, is the second most frequent cause of the congenital hyperinsulinism (CHI). Here, we reported a patient with normal birth weight, repeated seizures, untreatable hypoglycemia, and persistent, mild hyperammonemia. The genetic diagnosis revealed that the patient carried a heterozygous, de novo missense mutation (N410I, c.1401A>T) in the glutamate dehydrogenase 1 gene (

scholarly journals Zone of Polarizing Activity Regulatory Sequence Mutations/Duplications with Preaxial Polydactyly and Longitudinal Preaxial Ray Deficiency in the Phenotype: A Review of Human Cases, Animal Models, and Insights Regarding the Pathogenesis

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Mohammad M. Al-Qattan
Keyword(s):  
Developmental Biology ◽  
Animal Models ◽  
Sonic Hedgehog ◽  
Ectopic Expression ◽  
Point Mutations ◽  
Limb Bud ◽  
Regulatory Sequence ◽  
Preaxial Polydactyly ◽  
Zone Of Polarizing Activity

Clinicians and scientists interested in developmental biology have viewed preaxial polydactyly (PPD) and longitudinal preaxial ray deficiency (LPAD) as two different entities. Point mutations and duplications in the zone of polarizing activity regulatory sequence (ZRS) are associated with anterior ectopic expression of Sonic Hedgehog (SHH) in the limb bud and usually result in a PPD phenotype. However, some of these mutations/duplications also have LPAD in the phenotype. This unusual PPD-LPAD association in ZRS mutations/duplications has not been specifically reviewed in the literature. The author reviews this unusual entity and gives insights regarding its pathogenesis.

scholarly journals A Novel USH2A Variant in a Patient with Hearing Loss and Prenatal Diagnosis of a Familial Fetus: a Case Report and Literature Review

2020 ◽  
Author(s):  
Cong Zhou ◽  
Yuanyuan Xiao ◽  
Hanbing Xie ◽  
Shanling Liu ◽  
Jing Wang
Keyword(s):  
Hearing Loss ◽  
Prenatal Diagnosis ◽  
Novel Mutation ◽  
Relevant Literature ◽  
Usher Syndrome ◽  
Genetic Diagnosis ◽  
Screening Strategy ◽  
Chinese Patient ◽  
Gene Panel ◽  
Compound Heterozygous

Abstract Background: Usher syndrome (USH) is the most common cause of inherited deaf-blindness. This study aimed to identify pathogenic mutations in a Chinese patient with hearing loss and reviewed the relevant literature.Methods: Genomic DNA obtained from a five-year-old girl with hearing loss was analyzed via the disease-targeted gene panel. Results: We identified the compound heterozygous mutations c.8559-2A>G and c.4749delT in Usher syndrome type 2A (USH2A) gene as the underlying cause of the familial hearing loss; the former variation has been reported in the literature, but not the latter. The parents of the girl were heterozygous carriers. The two variants were pathogenic. Based on these findings, amniotic fluid samples were used for prenatal diagnosis of the couple's fetus, which was found to carry c.4749delT but not c.8559-2A>G variation. During the follow-up period of more than 9 months after the birth of the fetus, it was confirmed that the infant was healthy.Conclusions: We performed genetic diagnosis of Usher syndrome by disease-targeted gene panel and have proven that this method can serve as a rapid, high-throughput, and efficient screening strategy. The novel mutation expands the spectrum of USH2A variants in USH.

scholarly journals A novel mutation (g.106737G>T) in zone of polarizing activity regulatory sequence (ZRS) causes variable limb phenotypes in Werner mesomelia

2014 ◽  
Vol 164 (4) ◽  
pp. 898-906 ◽  
Author(s):  
Katta M. Girisha ◽  
Abdul Mueed Bidchol ◽  
Preeti S. Kamath ◽  
Krupa H. Shah ◽  
Geert R. Mortier ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Regulatory Sequence ◽  
Zone Of Polarizing Activity

scholarly journals Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes

2020 ◽  
Vol 57 (10) ◽  
pp. 660-663
Author(s):  
Jacob W P Potuijt ◽  
Jeannette Hoogeboom ◽  
Esther de Graaff ◽  
Christianne A van Nieuwenhoven ◽  
Robert Jan H Galjaard
Keyword(s):  
Sonic Hedgehog ◽  
Clinical Examination ◽  
Regulatory Element ◽  
Family Members ◽  
Limb Bud ◽  
Regulatory Sequence ◽  
Variable Expression ◽  
Zone Of Polarizing Activity ◽  
Reduced Penetrance ◽  
Triphalangeal Thumb

BackgroundThe of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause triphalangeal thumb (TPT) and polydactyly in affected families.ObjectiveIn this report, we describe two families with mild phenotypical presentation.MethodsWe performed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing.ResultsIn family I, a novel 165A>G variant in the ZRS (g.156584405A>G, GRCh37/Hg19) was found. In family II, we identified a 295T>C variant in the ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who were presumed to be unaffected shared the variant in the ZRS with affected family members, suggesting reduced penetrance of the genotype. However, clinical examination of these unaffected family members revealed minor anomalies like broad thumbs and lack of thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that these ZRS variants are minimally disruptive for Sonic Hedgehog expression and therefore can result in subclinical phenotypes.ConclusionOur study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.

scholarly journals Prenatal diagnosis of Duchenne muscular dystrophy revealed a novel mosaic mutation in Dystrophin gene: a case report

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yan Wang ◽  
Yuhan Chen ◽  
San Mei Wang ◽  
Xin Liu ◽  
Ya Nan Gu ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Sanger Sequencing ◽  
De Novo ◽  
Novel Mutation ◽  
Neuromuscular Disorders ◽  
Genetic Diagnosis ◽  
Dystrophin Gene ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Dmd Gene

Abstracts Background Duchenne muscular dystrophies (DMDs) are X-linked recessive neuromuscular disorders with malfunction or absence of the Dystrophin protein. Precise genetic diagnosis is critical for proper planning of patient care and treatment. In this study, we described a Chinese family with mosaic DMD mutations and discussed the best method for prenatal diagnosis and genetic counseling of X-linked familial disorders. Methods We investigated all variants of the whole dystrophin gene using multiple DNA samples isolated from the affected family and identified two variants of the DMD gene in a sick boy and two female carriers by targeted next generation sequencing (TNGS), Sanger sequencing, and haplotype analysis. Results We identified the hemizygous mutation c.6794delG (p.G2265Efs*6) of DMD in the sick boy, which was inherited from his mother. Unexpectedly, a novel heterozygous mutation c.6796delA (p.I2266Ffs*5) of the same gene, which was considered to be a de novo variant, was detected from his younger sister instead of his mother by Sanger sequencing. However, further NGS analysis of the mother and her amniotic fluid samples revealed that the mother carried a low-level mosaic c.6796delA mutation. Conclusions We reported two different mutations of the DMD gene in two siblings, including the novel mutation c.6796delA (p.I2266Ffs*5) inherited from the asymptomatic mosaic-carrier mother. This finding has enriched the knowledge of the pathogenesis of DMD. If no mutation is detected in obligate carriers, the administration of intricate STR/NGS/Sanger analysis will provide new ideas on the prenatal diagnosis of DMD.

scholarly journals Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

2020 ◽  
Vol 28 (12) ◽  
pp. 1763-1768
Author(s):  
Thomas Bourinaris ◽  
◽  
Damian Smedley ◽  
Valentina Cipriani ◽  
Isabella Sheikh ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
De Novo ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Spastic Paraplegia ◽  
Sequencing Data ◽  
Juvenile Form ◽  
Pathogenic Variants ◽  
Degenerative Disorders ◽  
Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

scholarly journals Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

2021 ◽  
Vol 21 (4) ◽  
Author(s):  
Lydia Saputra ◽  
Kishore Raj Kumar
Keyword(s):  
Genetic Diagnosis ◽  
Spastic Paraplegia ◽  
Limb Weakness ◽  
Hereditary Spastic Paraplegias ◽  
Gene Testing ◽  
Testing Strategies ◽  
Whole Exome ◽  
The Right ◽  
Gene Panels ◽  
High Degree

Abstract Purpose of Review The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP. Recent Findings There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Summary Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

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