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Jane A Evans - One of the best experts on this subject based on the ideXlab platform.
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the association of split hand Foot Malformation shfm and congenital heart defects
Birth Defects Research Part A-clinical and Molecular Teratology, 2008Co-Authors: Alison M Elliott, Jane A EvansAbstract:BACKGROUND: Split hand Foot Malformation (SHFM) (cleft hand, central ray deficiency) is a highly variable Malformation that shows genetic heterogeneity with at least five loci mapped to date. SHFM occurs as an isolated finding or in association with other anomalies, including congenital heart defects (CHDs). METHODS: In total 48 SHFM1, 52 SHFM3, 48 SHFM4, 21 SHFM5, and four chromosome 8 patients were evaluated. In addition, we performed a literature review to identify “unmapped” SHFM patients with CHD to evaluate the various etiologies of this combination of findings. The London Dysmorphology Database also served as a resource to identify syndromes with this combination of phenotypic findings. Only patients presenting with both SHFM and CHD were included in the analysis. Classification of CHD among mapped and unmapped SHFM patients was performed utilizing the revised Clark classification. A closer inspection of the types of CHD found in this patient group was performed in order to investigate possible pathogenetic mechanisms. RESULTS: CHDs were found in 10% of SHFM1 patients, 47% of SHFM5 patients, but were not reported in SHFM2, SHFM4 patients, or patients mapped to chromosome 8. Forty-two syndromic cases and 15 cases of unrecognized syndromes were identified. CONCLUSIONS: The higher frequency of heart defects seen in SHFM1 and SHFM5 of the mapped patient group raises the question as to whether common mechanisms/genetic players are involved. Candidate genes for SHFM1 and SHFM5 include members of the DLX homeobox gene family. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc.
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genotype phenotype correlations in mapped split hand Foot Malformation shfm patients
American Journal of Medical Genetics Part A, 2006Co-Authors: Alison M Elliott, Jane A EvansAbstract:Split hand Foot Malformation (SHFM) also known as central ray deficiency, ectrodactyly and cleft hand/Foot, is one of the most complex of limb Malformations. SHFM can occur as an isolated Malformation or in association with other Malformations, as in the ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome and other autosomal dominant conditions with long bone involvement, all showing variable expressivity and reduced penetrance. The deficiency in SHFM patients can also be accompanied by other distal limb anomalies including polydactyly and/or syndactyly. This variability causes the phenotypic classification of SHFM to be far from straightforward and genetic heterogeneity, with at least five loci identified to date, further complicates management of affected patients and their families. Although genotypic-phenotypic correlations have been proposed at the molecular level for SHFM4 patients who have mutations in the P63 gene, phenotypic correlations at the chromosomal level have not been thoroughly documented. Using descriptive epidemiology, Chi square and discriminant function analyses, our laboratory has identified phenotypic patterns associated with the mapped genetic SHFM loci. These findings can assist in classification, provide insight into responsible developmental genes and assist in directing mapping efforts and targeted genetic testing, resulting in more accurate information for family members in the clinical setting. Comparison with relevant animal models is discussed.
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clinical and epidemiological findings in patients with central ray deficiency split hand Foot Malformation shfm in manitoba canada
American Journal of Medical Genetics Part A, 2006Co-Authors: Alison M Elliott, Martin H Reed, Jane A Evans, Albert E Chudley, Bernard N ChodirkerAbstract:We conducted a clinical population study to examine the incidence and epidemiology of split hand Foot-Malformation (SHFM) in Manitoba from 1957 to 2003. The total number of births during this period was 850,742. Forty-three patients with SHFM were identified, resulting in an incidence of 1 in 19,784 births. Most patients were ascertained through referrals to the Section of Genetics and Metabolism at the Children's Hospital, Winnipeg, Manitoba. Overall, 22 (51.2%) of affected individuals were females and 21 (48.8%) were male. The left upper limb (LUL) was the most frequently affected, (in 46.5% of patients). The right hand was involved in 39.5%. In 4 patients (9.3%) all four limbs were affected. SHFM is classified as a failure of formation of parts according to the International Federation of Surgical Societies of the Hand (IFSSH) and has also been categorized as Typical or Atypical. Individuals in the Manitoba cohort were classified into two main categories: Typical (29 cases) and Atypical (3 cases). However, 11 patients were not easily placed into either group and comprised a distinct category termed “difficult to classify.” Patients in the three groups were then further subdivided depending on whether or not they had additional congenital anomalies. These complex patients included those with single gene disorders in which SHFM has been reported (e.g., ectodermal dysplasia Ectrodactyly Clefting (EEC), tibial aplasia with SHFM, fibular aplasia with SHFM), as well as those with other recognized or unknown patterns of anomalies. Two had deletions involving 9q and 5p respectively. Unlike some other studies, we did not find an excess of males or right-sided defects and only two of the cases—two sisters—were related. © 2006 Wiley-Liss, Inc.
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split hand Foot Malformation shfm
Clinical Genetics, 2005Co-Authors: Alison M Elliott, Jane A Evans, Albert E ChudleyAbstract:The nomenclature describing the phenotype of missing central rays in the hand and/or Foot in the genetics and surgical literature is heterogeneous and confusing. Split hand/Foot Malformation (SHFM) is the most common term for this phenotype in the genetics community; however, other names such as the offensive 'lobster-claw Malformation' and the non-specific 'ectrodactyly' are still utilized to describe this Malformation. In this article, we briefly review the nomenclature associated with SHFM and its classifications.
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discrepancies in upper and lower limb patterning in split hand Foot Malformation
Clinical Genetics, 2005Co-Authors: Alison M Elliott, Martin H Reed, Tony Roscioli, Jane A EvansAbstract:Discrepancies in upper and lower limb patterning in split hand Foot Malformation. Split hand Foot Malformation (SHFM) is genetically heterogeneous with five loci mapped to date. Highly variable in presentation, it can occur as an isolated finding or with other anomalies. The genetic heterogeneity and clinical variability make genetic counselling of SHFM families challenging. By establishing genotype/phenotype correlations, one can provide insight into responsible developmental genes and help to direct mapping efforts and target genetic testing, ultimately providing more accurate information for family members. Preaxial involvement of the upper extremities was a significant discriminating limb-specific variable in our analysis of genetically mapped SHFM cases. This finding, which was originally identified through descriptive epidemiology, was subsequently confirmed by discriminant function analysis (p < 0.0001) to be a significant locus discriminator. Preaxial involvement of the upper extremities was most commonly seen at the SHFM3 locus mapped to chromosome 10q24 (OMIM 600095) and consisted of proximally placed thumbs and/or triphalangeal thumbs (TPT), preaxial polydactyly and/or absence of the first ray. These patients' feet, however, tended to show a classical central longitudinal deficiency without a significant preaxial component. This article discusses this discrepant clefting pattern between the upper and lower extremities and proposes potential mechanisms.
Wasim Ahmad - One of the best experts on this subject based on the ideXlab platform.
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a novel homozygous nonsense mutation p cys366 in the wnt10b gene underlying split hand split Foot Malformation in a consanguineous pakistani family
Frontiers in Pediatrics, 2020Co-Authors: Muhammad Umair, Wasim Ahmad, Muhammad Ansar, Amjad Khan, Rongrong Wang, Shirui Han, Mohammad A Alshabeeb, Manal AlaameryAbstract:Abstract Split hand/split Foot Malformation (SHFM) or ectrodactyly is characterized by a deep median cleft of the hand or Foot, hypoplasia or aplasia of the metacarpals, metatarsals, and phalanges. It is a clinically and genetically heterogeneous group of limb Malformations. This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive SHFM. Peripheral blood samples were obtained, DNA was extracted, WNT10B coding and noncoding regions were PCR amplified and Sanger sequencing was performed using workflow suggested by Thermo Fisher Scientific. A novel homozygous nonsense variant (c.1098C>A; p.Cys366*) was identified in the WNT10B gene in the index patients, which probably explains SHFM type 6 in this family in comparison with similar data from the literature.
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first direct evidence of involvement of a homozygous loss of function variant in the eps15l1 gene underlying split hand split Foot Malformation
Clinical Genetics, 2018Co-Authors: Muhammad Umair, Asmat Ullah, Farooq Ahmad, Sulman Basit, Safdar Abbas, Wasim AhmadAbstract:Split-hand/split-Foot Malformation (SHFM) is a severe form of congenital limb deformity characterized by the absence of 1 or more digits and/or variable degree of median clefts of hands and feet. The present study describes an investigation of a consanguineous family of Pakistani origin segregating SHFM in an autosomal recessive manner. Human genome scan using SNP markers followed by whole exome sequencing revealed a frameshift deletion (c.409delA, p.Ser137Alafs*19) in the EPS15L1 gene located on chromosome 19p13.11. This is the first biallelic variant identified in the EPS15L1 gene underlying SHFM. Our findings report the first direct involvement of EPS15L1 gene in the development of human limbs.
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homozygous sequence variants in the wnt10b gene underlie split hand Foot Malformation
Genetics and Molecular Biology, 2018Co-Authors: Asmat Ullah, Ajab Gul, Muhammad Umair, Farooq Ahmad, Abdul Aziz, Abdul Wali, Wasim AhmadAbstract:Split-hand/split-Foot Malformation (SHFM), also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb Malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D) segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1-q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154*) in exon 4 of the WNT10B gene in two families (A and B). In the other two families (C and D), a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53) was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/Foot Malformation.
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Homozygous sequence variants in the WNT10B gene underlie split hand/Foot Malformation
Sociedade Brasileira de Genética, 2018Co-Authors: Asmat Ullah, Ajab Gul, Muhammad Umair, Farooq Ahmad, Abdul Aziz, Abdul Wali, Wasim AhmadAbstract:Abstract Split-hand/split-Foot Malformation (SHFM), also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb Malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D) segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1–q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154*) in exon 4 of the WNT10B gene in two families (A and B). In the other two families (C and D), a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53) was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/Foot Malformation
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a novel heterozygous intragenic sequence variant in dlx6 probably underlies first case of autosomal dominant split hand Foot Malformation type 1
Molecular Syndromology, 2017Co-Authors: Asmat Ullah, Muhammad Umair, Anam Hammid, Wasim AhmadAbstract:Split-hand and Foot Malformation (SHFM; MIM 183600) is a rare human genetic limb Malformation. It is characterized by missing digital rays in the hands and feet. SHFMs vary in severity from mild abnormalities affecting a single limb to acute Malformations involving all 4 limbs. It is inherited, as part of both a syndromic and nonsyndromic disorder, in an autosomal recessive, autosomal dominant, and X-linked patterns. So far, 9 loci of hand and Foot Malformation have been mapped on human chromosomes. The present study describes a family with 2 affected individuals segregating SHFM in an autosomal dominant fashion. Sanger sequencing of the genes involved in SHFM was performed to identify the disease-causing variant. Sequence analysis revealed the first heterozygous missense variant (c.632T>A, p.Val211Glu) in the distal-less homeobox 6 (DLX6) gene, located in chromosome 7q21, causing SHFM in the present family. This study supports the evidence of DLX6 as an SHFM-causing gene.
Fiorella Gurrieri - One of the best experts on this subject based on the ideXlab platform.
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clinical genetic and molecular aspects of split hand Foot Malformation an update
American Journal of Medical Genetics Part A, 2013Co-Authors: Fiorella Gurrieri, David B EvermanAbstract:We here provide an update on the clinical, genetic, and molecular aspects of split-hand/Foot Malformation (SHFM). This rare condition, affecting 1 in 8,500–25,000 newborns, is extremely complex because of its variability in clinical presentation, irregularities in its inheritance pattern, and the heterogeneity of molecular genetic alterations that can be found in affected individuals. Both syndromal and nonsyndromal forms are reviewed and the major molecular genetic alterations thus far reported in association with SHFM are discussed. This updated overview should be helpful for clinicians in their efforts to make an appropriate clinical and genetic diagnosis, provide an accurate recurrence risk assessment, and formulate a management plan. © 2013 Wiley Periodicals, Inc.
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frequency of genomic rearrangements involving the shfm3 locus at chromosome 10q24 in syndromic and non syndromic split hand Foot Malformation
American Journal of Medical Genetics Part A, 2006Co-Authors: David B Everman, Fiorella Gurrieri, Michael J Bamshad, Chad T Morgan, Robert Lyle, Katie Clarkson, R S Colby, Mary E Laughridge, Micheil A Innes, Jacquelyn RobersonAbstract:Split-hand/Foot Malformation (SHFM), or ectrodactyly, is characterized by underdeveloped or absent central digital rays, clefts of the hands and feet, and variable syndactyly of the remaining digits. SHFM occurs as both an isolated finding and a component of many syndromes. SHFM is a heterogeneous condition caused by multiple loci, including SHFM1 (chromosome region 7q21-q22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). Mutations in TP63 at the SHFM4 locus are known to underlie both syndromic and non-syndromic forms SHFM, but the causes of most non-syndromic SHFM cases remain unknown. The recent identification of submicroscopic tandem chromosome duplications affecting the SHFM3 locus in seven families with non-syndromic SHFM has helped to further unravel the molecular basis of this Malformation. In our ongoing studies of the SHFM3 locus in 44 additional cases of syndromic and non-syndromic SHFM, we have identified similar chromosome rearrangements in eight additional cases (18%), using pulsed-field gel electrophoresis (PFGE). We have also utilized real-time quantitative PCR (qPCR) to test for the duplications. Seven of the cases with rearrangements were non-syndromic. The current findings bring the total of SHFM3-associated cases with chromosome rearrangements to 15, which constitute 29% (15 of 51) of the cases screened to date. This includes 9 of 9 cases (100%) with known linkage to the SHFM3 locus, all of whom have non-syndromic SHFM, and 6 of 42 additional cases (14%), four of whom have non-syndromic SHFM. Thus, SHFM3 abnormalities underlie a substantial proportion of SHFM cases and appear to be a more frequent cause of non-syndromic SHFM than mutations in TP63.
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a genomic rearrangement resulting in a tandem duplication is associated with split hand split Foot Malformation 3 shfm3 at 10q24
Human Molecular Genetics, 2003Co-Authors: Xavier J De Mollerat, Eugenio Sangiorgi, Fiorella Gurrieri, Michael J Bamshad, David B Everman, Chad T Morgan, Paola Gaspari, Jeanne Amiel, Robert Lyle, Jeanlouis BlouinAbstract:Split hand-split Foot Malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed.
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genomic organization and embryonic expression of suppressor of fused a candidate gene for the split hand split Foot Malformation type 3
FEBS Letters, 2001Co-Authors: Thomas Grimm, Eugenio Sangiorgi, Fiorella Gurrieri, Charles E Schwartz, Stephan Teglund, Darci Tackels, Rune ToftgardAbstract:The genes for human and mouse Suppressor of Fused (SU(FU)/Su(Fu)) in the Hedgehog signaling pathway were characterized and found to contain 12 exons. Human SU(FU) localized on chromosome 10q24–25 between the markers D10S192 and AFM183XB12. We detected three additional SU(FU) isoforms, two of which have lost their ability to interact with the transcription factor GLI1. Expression analysis using whole mount in situ hybridization revealed strong expression of Su(Fu) in various mouse embryonic tissues. SU(FU) was considered a candidate gene for the split-hand/split-Foot Malformation type 3 (SHFM3). However, no alterations in the SU(FU) gene were found in SHFM3 patients.
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p63 gene mutations in eec syndrome limb mammary syndrome and isolated split hand split Foot Malformation suggest a genotype phenotype correlation
American Journal of Human Genetics, 2001Co-Authors: Hans Van Bokhoven, Ben C J Hamel, Eugenio Sangiorgi, Fiorella Gurrieri, Pascal H G Duijf, Kaate R J Vanmolkot, Ellen Van Beusekom, Sylvia E C Van Beersum, Michael J Bamshad, Jacopo CelliAbstract:p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand–split Foot Malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3′ splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.
Alison M Elliott - One of the best experts on this subject based on the ideXlab platform.
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the association of split hand Foot Malformation shfm and congenital heart defects
Birth Defects Research Part A-clinical and Molecular Teratology, 2008Co-Authors: Alison M Elliott, Jane A EvansAbstract:BACKGROUND: Split hand Foot Malformation (SHFM) (cleft hand, central ray deficiency) is a highly variable Malformation that shows genetic heterogeneity with at least five loci mapped to date. SHFM occurs as an isolated finding or in association with other anomalies, including congenital heart defects (CHDs). METHODS: In total 48 SHFM1, 52 SHFM3, 48 SHFM4, 21 SHFM5, and four chromosome 8 patients were evaluated. In addition, we performed a literature review to identify “unmapped” SHFM patients with CHD to evaluate the various etiologies of this combination of findings. The London Dysmorphology Database also served as a resource to identify syndromes with this combination of phenotypic findings. Only patients presenting with both SHFM and CHD were included in the analysis. Classification of CHD among mapped and unmapped SHFM patients was performed utilizing the revised Clark classification. A closer inspection of the types of CHD found in this patient group was performed in order to investigate possible pathogenetic mechanisms. RESULTS: CHDs were found in 10% of SHFM1 patients, 47% of SHFM5 patients, but were not reported in SHFM2, SHFM4 patients, or patients mapped to chromosome 8. Forty-two syndromic cases and 15 cases of unrecognized syndromes were identified. CONCLUSIONS: The higher frequency of heart defects seen in SHFM1 and SHFM5 of the mapped patient group raises the question as to whether common mechanisms/genetic players are involved. Candidate genes for SHFM1 and SHFM5 include members of the DLX homeobox gene family. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc.
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genotype phenotype correlations in mapped split hand Foot Malformation shfm patients
American Journal of Medical Genetics Part A, 2006Co-Authors: Alison M Elliott, Jane A EvansAbstract:Split hand Foot Malformation (SHFM) also known as central ray deficiency, ectrodactyly and cleft hand/Foot, is one of the most complex of limb Malformations. SHFM can occur as an isolated Malformation or in association with other Malformations, as in the ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome and other autosomal dominant conditions with long bone involvement, all showing variable expressivity and reduced penetrance. The deficiency in SHFM patients can also be accompanied by other distal limb anomalies including polydactyly and/or syndactyly. This variability causes the phenotypic classification of SHFM to be far from straightforward and genetic heterogeneity, with at least five loci identified to date, further complicates management of affected patients and their families. Although genotypic-phenotypic correlations have been proposed at the molecular level for SHFM4 patients who have mutations in the P63 gene, phenotypic correlations at the chromosomal level have not been thoroughly documented. Using descriptive epidemiology, Chi square and discriminant function analyses, our laboratory has identified phenotypic patterns associated with the mapped genetic SHFM loci. These findings can assist in classification, provide insight into responsible developmental genes and assist in directing mapping efforts and targeted genetic testing, resulting in more accurate information for family members in the clinical setting. Comparison with relevant animal models is discussed.
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clinical and epidemiological findings in patients with central ray deficiency split hand Foot Malformation shfm in manitoba canada
American Journal of Medical Genetics Part A, 2006Co-Authors: Alison M Elliott, Martin H Reed, Jane A Evans, Albert E Chudley, Bernard N ChodirkerAbstract:We conducted a clinical population study to examine the incidence and epidemiology of split hand Foot-Malformation (SHFM) in Manitoba from 1957 to 2003. The total number of births during this period was 850,742. Forty-three patients with SHFM were identified, resulting in an incidence of 1 in 19,784 births. Most patients were ascertained through referrals to the Section of Genetics and Metabolism at the Children's Hospital, Winnipeg, Manitoba. Overall, 22 (51.2%) of affected individuals were females and 21 (48.8%) were male. The left upper limb (LUL) was the most frequently affected, (in 46.5% of patients). The right hand was involved in 39.5%. In 4 patients (9.3%) all four limbs were affected. SHFM is classified as a failure of formation of parts according to the International Federation of Surgical Societies of the Hand (IFSSH) and has also been categorized as Typical or Atypical. Individuals in the Manitoba cohort were classified into two main categories: Typical (29 cases) and Atypical (3 cases). However, 11 patients were not easily placed into either group and comprised a distinct category termed “difficult to classify.” Patients in the three groups were then further subdivided depending on whether or not they had additional congenital anomalies. These complex patients included those with single gene disorders in which SHFM has been reported (e.g., ectodermal dysplasia Ectrodactyly Clefting (EEC), tibial aplasia with SHFM, fibular aplasia with SHFM), as well as those with other recognized or unknown patterns of anomalies. Two had deletions involving 9q and 5p respectively. Unlike some other studies, we did not find an excess of males or right-sided defects and only two of the cases—two sisters—were related. © 2006 Wiley-Liss, Inc.
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split hand Foot Malformation shfm
Clinical Genetics, 2005Co-Authors: Alison M Elliott, Jane A Evans, Albert E ChudleyAbstract:The nomenclature describing the phenotype of missing central rays in the hand and/or Foot in the genetics and surgical literature is heterogeneous and confusing. Split hand/Foot Malformation (SHFM) is the most common term for this phenotype in the genetics community; however, other names such as the offensive 'lobster-claw Malformation' and the non-specific 'ectrodactyly' are still utilized to describe this Malformation. In this article, we briefly review the nomenclature associated with SHFM and its classifications.
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discrepancies in upper and lower limb patterning in split hand Foot Malformation
Clinical Genetics, 2005Co-Authors: Alison M Elliott, Martin H Reed, Tony Roscioli, Jane A EvansAbstract:Discrepancies in upper and lower limb patterning in split hand Foot Malformation. Split hand Foot Malformation (SHFM) is genetically heterogeneous with five loci mapped to date. Highly variable in presentation, it can occur as an isolated finding or with other anomalies. The genetic heterogeneity and clinical variability make genetic counselling of SHFM families challenging. By establishing genotype/phenotype correlations, one can provide insight into responsible developmental genes and help to direct mapping efforts and target genetic testing, ultimately providing more accurate information for family members. Preaxial involvement of the upper extremities was a significant discriminating limb-specific variable in our analysis of genetically mapped SHFM cases. This finding, which was originally identified through descriptive epidemiology, was subsequently confirmed by discriminant function analysis (p < 0.0001) to be a significant locus discriminator. Preaxial involvement of the upper extremities was most commonly seen at the SHFM3 locus mapped to chromosome 10q24 (OMIM 600095) and consisted of proximally placed thumbs and/or triphalangeal thumbs (TPT), preaxial polydactyly and/or absence of the first ray. These patients' feet, however, tended to show a classical central longitudinal deficiency without a significant preaxial component. This article discusses this discrepant clefting pattern between the upper and lower extremities and proposes potential mechanisms.
David B Everman - One of the best experts on this subject based on the ideXlab platform.
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clinical genetic and molecular aspects of split hand Foot Malformation an update
American Journal of Medical Genetics Part A, 2013Co-Authors: Fiorella Gurrieri, David B EvermanAbstract:We here provide an update on the clinical, genetic, and molecular aspects of split-hand/Foot Malformation (SHFM). This rare condition, affecting 1 in 8,500–25,000 newborns, is extremely complex because of its variability in clinical presentation, irregularities in its inheritance pattern, and the heterogeneity of molecular genetic alterations that can be found in affected individuals. Both syndromal and nonsyndromal forms are reviewed and the major molecular genetic alterations thus far reported in association with SHFM are discussed. This updated overview should be helpful for clinicians in their efforts to make an appropriate clinical and genetic diagnosis, provide an accurate recurrence risk assessment, and formulate a management plan. © 2013 Wiley Periodicals, Inc.
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a new locus for split hand Foot Malformation with long bone deficiency shfld at 2q14 2 identified from a chromosome translocation
Human Genetics, 2007Co-Authors: Christian Babbs, Charles E Schwartz, David B Everman, Raoul Heller, M Crocker, Stephen R F Twigg, Henk Giele, Andrew O M WilkieAbstract:Split hand/Foot Malformation (SHFM) with long bone deficiency (SHFLD) is a distinct entity in the spectrum of ectrodactylous limb Malformations characterised by associated tibial a/hypoplasia. Pedigrees with multiple individuals affected by SHFLD often include non-penetrant intermediate relatives, making genetic mapping difficult. Here we report a sporadic patient with SHFLD who carries a de novo chromosomal translocation t(2;18)(q14.2;p11.2). Characterisation of the breakpoints revealed that neither disrupts any known gene; however, the chromosome 2 breakpoint lies between GLI2 and INHBB, two genes known to be involved in limb development. To investigate whether mutation of a gene in proximity to the chromosome 2 breakpoint underlies the SHFLD, we sought independent evidence of mutations in GLI2, INHBB and two other genes (RALB and FLJ14816) in 44 unrelated patients with SHFM, SHFLD or isolated long bone deficiency. No convincing pathogenic mutations were found, raising the possibility that a long-range cis acting regulatory element may be disrupted by this translocation. The previous description of a translocation with a 2q14.2 breakpoint associated with ectrodactyly, and the mapping of the ectrodactylous Dominant hemimelia mouse mutation to a region of homologous synteny, suggests that 2q14.2 represents a novel locus for SHFLD.
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split hand split Foot Malformation 3 shfm3 at 10q24 development of rapid diagnostic methods and gene expression from the region
American Journal of Medical Genetics Part A, 2006Co-Authors: Robert Lyle, David B Everman, Jeanlouis Blouin, Uppala Radhakrishna, Sarantis Gagos, Corinne Gehrig, C D Delozierblanchet, Jitendra V Solanki, Uday C Patel, Swapan K NathAbstract:Split-hand/split-Foot Malformation (SHFM, also called ectrodactyly) is a clinically variable and genetically heterogeneous group of limb Malformations. Several SHFM loci have been mapped, including SHFM1 (7q21), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27) and SHFM5 (2q31). To date, mutations in a gene (TP63) have only been identified for SHFM4. SHFM3 has been shown by pulsed-field gel electrophoresis to be caused by an approximately 500 kb DNA rearrangement at 10q24. This region contains a number of candidate genes for SHFM3, though which gene(s) is (are) involved in the pathogenesis of SHFM3 is not known. Our aim in this study was to improve the diagnosis of SHFM3, and to begin to understand which genes are involved in SHFM3. Here we show, using two different techniques, FISH and quantitative PCR that SHFM3 is caused by a minimal 325 kb duplication containing only two genes (BTRC and POLL). The data presented provide improved methods for diagnosis and begin to elucidate the pathogenic mechanism of SHFM3. Expression analysis of 13 candidate genes within and flanking the duplicated region shows that BTRC (present in three copies) and SUFU (present in two copies) are overexpressed in SHFM3 patients compared to controls. Our data suggest that SHFM3 may be caused by overexpression of BTRC and SUFU, both of which are involved in beta-catenin signalling.
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frequency of genomic rearrangements involving the shfm3 locus at chromosome 10q24 in syndromic and non syndromic split hand Foot Malformation
American Journal of Medical Genetics Part A, 2006Co-Authors: David B Everman, Fiorella Gurrieri, Michael J Bamshad, Chad T Morgan, Robert Lyle, Katie Clarkson, R S Colby, Mary E Laughridge, Micheil A Innes, Jacquelyn RobersonAbstract:Split-hand/Foot Malformation (SHFM), or ectrodactyly, is characterized by underdeveloped or absent central digital rays, clefts of the hands and feet, and variable syndactyly of the remaining digits. SHFM occurs as both an isolated finding and a component of many syndromes. SHFM is a heterogeneous condition caused by multiple loci, including SHFM1 (chromosome region 7q21-q22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). Mutations in TP63 at the SHFM4 locus are known to underlie both syndromic and non-syndromic forms SHFM, but the causes of most non-syndromic SHFM cases remain unknown. The recent identification of submicroscopic tandem chromosome duplications affecting the SHFM3 locus in seven families with non-syndromic SHFM has helped to further unravel the molecular basis of this Malformation. In our ongoing studies of the SHFM3 locus in 44 additional cases of syndromic and non-syndromic SHFM, we have identified similar chromosome rearrangements in eight additional cases (18%), using pulsed-field gel electrophoresis (PFGE). We have also utilized real-time quantitative PCR (qPCR) to test for the duplications. Seven of the cases with rearrangements were non-syndromic. The current findings bring the total of SHFM3-associated cases with chromosome rearrangements to 15, which constitute 29% (15 of 51) of the cases screened to date. This includes 9 of 9 cases (100%) with known linkage to the SHFM3 locus, all of whom have non-syndromic SHFM, and 6 of 42 additional cases (14%), four of whom have non-syndromic SHFM. Thus, SHFM3 abnormalities underlie a substantial proportion of SHFM cases and appear to be a more frequent cause of non-syndromic SHFM than mutations in TP63.
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a genomic rearrangement resulting in a tandem duplication is associated with split hand split Foot Malformation 3 shfm3 at 10q24
Human Molecular Genetics, 2003Co-Authors: Xavier J De Mollerat, Eugenio Sangiorgi, Fiorella Gurrieri, Michael J Bamshad, David B Everman, Chad T Morgan, Paola Gaspari, Jeanne Amiel, Robert Lyle, Jeanlouis BlouinAbstract:Split hand-split Foot Malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed.