William Reardon - Academia.edu (original) (raw)

Papers by William Reardon

Research paper thumbnail of Cerebellar ataxia and ectodermal dysplasia in brothers

Journal of Medical Genetics, Jun 1, 1993

Two brothers are documented with an ectodermal dysplasia primarily involving the teeth and hair. ... more Two brothers are documented with an ectodermal dysplasia primarily involving the teeth and hair. Both have developed cerebellar ataxia in the early teens. (J Med Genet 1993;30:515-17) The association of a cerebellar ataxia and an ectodermal dysplasia is unusual, and has only been reported in seven patients.'-3 Ectodermal features have generally been confined to hair and teeth with the cerebellar ataxia being later in onset and progressive in nature. The main additional clinical features have varied from one report to another and have included mental retardation, short stature, deafness, and hypogonadism. We now report a further sibship with this rare entity but with normal intelligence, and review this group of conditions.

Research paper thumbnail of The 12q14 microdeletion syndrome: Additional patients and further evidence that HMGA2 is an important genetic determinant for human height

European Journal of Medical Genetics, Apr 1, 2009

Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to ... more Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to thrive, short stature, learning disabilities and Buschke-Ollendorff lesions in bone and skin. This report on two additional patients with this microdeletion syndrome emphasizes the rather constant and uniform phenotype encountered in this disorder and refines the critical region to a 2.61 Mb interval on 12q14.3, encompassing 10 RefSeq genes. We have previously shown that LEMD3 haploinsufficiency is responsible for the Buschke-Ollendorff lesions and now provide strong evidence that a heterozygous deletion of HMGA2 is causing the growth failure observed in this disorder. The identification of an intragenic HMGA2 deletion in a boy with proportionate short stature and the cosegregation of this deletion with reduced adult height in the extended family of the boy further underscore the role of HMGA2 in regulating human linear growth.

Research paper thumbnail of Evidence for locus heterogeneity in acrocephalosyndactyly: A refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p-and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p and 5q

Amer J Hum Genet, 1994

Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous gro... more Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous group of disorders, frequently involving digital abnormalities. We have previously provisionally assigned the gene for one such condition, Saethre-Chotzen syndrome (ACS III), to chromosome 7p. Linkage analysis is now reported between ACS III and dinucleotide repeat loci on distal 7p. The maximum lod scores, Zmax, were 5.57 at a recombination fraction of .05, with D7S488, and 4.74 at a recombination fraction of .05, with D7S493. Only weak linkage, not reaching significance, was found with distal markers (D7S513 and afm281vc9) and a proximal marker (D7S516). Multipoint analysis shows that the disease locus lies between D7S513 and D7S516. Analysis of individual recombinants shows that the most likely position is between D7S493 and D7S516. Linkage data in regard of Jackson-Weiss syndrome demonstrate that this autosomal dominant form of acrocephalosyndactyly does not map to the ACS III region on 7p or to the acrocephalosyndactyly locus on 5q (Boston type). These findings underline the genetic heterogeneity among the different clinical conditions manifesting with acrocephalosyndactyly.

Research paper thumbnail of Moebius sequence and hypogonadotrophic hypogonadism

American journal of medical genetics. Part A, Jan 15, 2003

A distinct form of Moebius sequence is associated with hypogonadotrophic hypogonadism. There have... more A distinct form of Moebius sequence is associated with hypogonadotrophic hypogonadism. There have been five such cases to date. We now add a further case with detailed neurologic, endocrine, and autopsy findings and offer a hypothesis drawing parallels with the already established basis of hypogonadotrophic hypogonadism in the X-linked form of Kallman syndrome.

Research paper thumbnail of Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis

Nature genetics, 1999

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the tr... more The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. T...

Research paper thumbnail of A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis

Nature genetics, 1998

Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal domin... more Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal dominant trait; association with anterior meningocoele, presacral teratoma and anorectal abnormalities constitutes the Currarino triad (MIM 176450). Malformation at the caudal end of the developing notochord at approximately Carnegie stage 7 (16 post-ovulatory days), which results in aberrant secondary neurulation, can explain the observed pattern of anomalies. We previously reported linkage to 7q36 markers in two dominantly inherited sacral agenesis families. We now present data refining the initial subchromosomal localization in several additional hereditary sacral agenesis (HSA) families. We excluded several candidate genes before identifying patient-specific mutations in a homeobox gene, HLXB9, which was previously reported to map to 1q41-q42.1 and to be expressed in lymphoid and pancreatic tissues.

Research paper thumbnail of Evidence for locus heterogeneity in acrocephalosyndactyly: a refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p--and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p and 5q

American journal of human genetics, 1994

Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous gro... more Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous group of disorders, frequently involving digital abnormalities. We have previously provisionally assigned the gene for one such condition, Saethre-Chotzen syndrome (ACS III), to chromosome 7p. Linkage analysis is now reported between ACS III and dinucleotide repeat loci on distal 7p. The maximum lod scores, Zmax, were 5.57 at a recombination fraction of .05, with D7S488, and 4.74 at a recombination fraction of .05, with D7S493. Only weak linkage, not reaching significance, was found with distal markers (D7S513 and afm281vc9) and a proximal marker (D7S516). Multipoint analysis shows that the disease locus lies between D7S513 and D7S516. Analysis of individual recombinants shows that the most likely position is between D7S493 and D7S516. Linkage data in regard of Jackson-Weiss syndrome demonstrate that this autosomal dominant form of acrocephalosyndactyly does not map to the ACS III region on...

Research paper thumbnail of Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis

Research paper thumbnail of Update on Kleefstra syndrome

Molecular Syndromology, 2012

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual dis... more Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

Research paper thumbnail of Enlarged vestibular aqueduct: a radiological marker of Pendred syndrome, and mutation of the PDS gene

QJM, 2000

Although the textbook view of Pendred syndrome is that of an autosomal recessive condition charac... more Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome. Since this is the most common radiological malformation of the cochlea in deaf patients, we investigated what proportion of such cases were due to mutation of the PDS gene. We assessed 57 patients referred with radiological evidence of vestibular aqueduct enlargement, by history, clinical examination, perchlorate discharge test and molecular analysis of the PDS locus. Forty-one patients (72%) had unequivocal evidence of Pendred syndrome. The finding of a single heterozygous mutation at the PDS gene in a further eight was strongly suggestive of a critical role for pendrin, the protein product of the PDS gene, in the generation of enlarged vestibular aqueducts in at least 86% (49/57 cases) of patients with this radiological malformation. Securing the diagnosis of Pendred syndrome may be difficult, especially in the single case. Goitre is an inconstant finding, and the perchlorate discharge test, although helpful, is of diagnostic value only if abnormal. Enlargement of the vestibular aqueduct should be considered as the most likely presentation of Pendred syndrome and should prompt specific investigation of that diagnostic possibility. Pendred syndrome might henceforth be recharacterized as deafness with enlargement of the vestibular aqueduct, which is sometimes associated with goitre.

Research paper thumbnail of Symptomatic anal anomalies in chromosome 22q11 deletion syndrome: a report of three patients

Pediatric Surgery International, 2006

Deletion of chromosome 22q11 is a common genetic condition with varying clinical presentation ran... more Deletion of chromosome 22q11 is a common genetic condition with varying clinical presentation ranging from neonatal fatality to patients whose presentation to medical services will be prompted after a few years by speech delay or mild developmental concerns. While most published data relating to patients with 22q11 deletions has focused on the ''classical'' presentation of the condition with cardiac manifestations, hypocalcaemia and velopharyngeal insufficiency, a much wider range of clinical presentations can characterise this syndrome. Anal anomalies, comprising imperforate anus and symptomatic anal stenosis, are a rarely described presentation of this multisystem disorder. In this report we document three patients presenting to paediatric services with symptoms attributed initially to symptomatic anal stenosis/atresia.

Research paper thumbnail of Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes

New England Journal of Medicine, 2008

BACKGROUND-Duplications and deletions in the human genome can cause disease or predispose persons... more BACKGROUND-Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.

Research paper thumbnail of X-linked deafness, stapes gushers and a distinctive defect of the inner ear

Neuroradiology, 1991

The association of X-linked mixed deafness with stapes gusher has been recognised for 20 years, m... more The association of X-linked mixed deafness with stapes gusher has been recognised for 20 years, mad imaging studies by polytomography have shown dilatation of the lateral end of the internal auditory meatus (IAM) in some cases. We have made genetic linkage studies in 7 pedigrees in whom deafness was inherited in an X-linked manner. All patients had a full range of audiometric and vestibular function tests. Thin section high resolution CT in two planes was used to assess the state of the middle and inner ears. We found a distinctive inner ear deformity in some of the deaf males characterised not only by a wide bulbous IAM but more importantly, by deficient or absent bone between the lateral end of the IAM and the basal turn of the cochlea. We believe that this results in a communication between the subarachnoid space in the IAM and the perilymph in the cochlea, leading to perilymphatic hydrops and a "gusher" if the stapes is disturbed. Moreover, some of the obligate female carriers seem to have a milder form of the same anomaly associated with slight hearing loss. Genetic studies on some of the deaf males with apparently normal inner ear anatomy suggest a different locus on the X chromosome and hence a different pathogenesis for the deafness.

Research paper thumbnail of Disordered Peripheral Nerve Conduction in DOOR(S) Syndrome

Neuropediatrics, 1994

A case of DOOR(S) syndrome is detailed and the neurophysiological abnormalities observed in this ... more A case of DOOR(S) syndrome is detailed and the neurophysiological abnormalities observed in this patient and in other cases with this rare but recognisable autosomal recessive condition are considered. Particular emphasis is paid to the abnormal peripheral nerve conduction, which has not previously been recorded in the condition.

Research paper thumbnail of Mutations in CDMP1 cause autosomal dominant brachydactyly type C

Research paper thumbnail of Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis

Journal of Medical Genetics, 2008

Patients with a microscopically visible deletion of the distal part of the long arm of chromosome... more Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects, as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. To describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and to report on the molecular characterisation of the deletion size. The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in 10 of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalities to a 360 kb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.

Research paper thumbnail of Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases

Journal of Medical Genetics, 2005

Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated... more Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. Methods: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. Results: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. Conclusions: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

Research paper thumbnail of Fluorescent in situ hybridisation (FISH) for hemizygous deletion at the elastin locus in patients with isolated supravalvular aortic stenosis

Journal of Medical Genetics, 1997

Both Williams syndrome and isolated supravalvular aortic stenosis (SVAS) are caused by mutations ... more Both Williams syndrome and isolated supravalvular aortic stenosis (SVAS) are caused by mutations at the elastin locus. Deletion demonstrable by FISH is the hallmark of Williams syndrome, whereas the mutations reported so far in SVAS have been more subtle. FISH positive elastin hemizygosity has not been reported in isolated SVAS. This report records our experience of FISH for elastin deletion in isolated SVAS and specifically reports a patient with non-Williams related SVAS, positive for the elastin deletion by FISH.

Research paper thumbnail of Close linkage of a gene for X linked deafness to three microsatellite repeats at Xq21 in radiologically normal and abnormal families

Journal of Medical Genetics, 1994

We have used three highly polymorphic microsatellite repeats from Xq21 to type families in whom a... more We have used three highly polymorphic microsatellite repeats from Xq21 to type families in whom a gene for X linked deafness with perilymphatic gusher (DFN 3) was segregating. All three markers were tightly linked to the disease in its radiologically normal and abnormal forms, with a maximum lod score of 10.37 with DXS995 and 8.44 with DXS986 at zero recombination, and 14.03 with DXS1002 at theta = 0.01. In an isolated case of deafness of this type, DXS995 indicated either the first recombination observed between the marker and the disease gene or a new mutation in the proband. Southern blotting using a cosmid fragment from the candidate region has confirmed a de novo mutation by showing a deletion in the proband which is not present in his mother as judged by dosage analysis. We also describe a family with a paracentric inversion associated with a microdeletion and discuss how deletion mapping using these and other markers in the region has helped to define a candidate region for the gene.

Research paper thumbnail of Crouzon syndrome is not linked to craniosynostosis loci at 7p and 5qter

Journal of Medical Genetics, 1994

Evidence for linkage has been sought, in four pedigrees with Crouzon syndrome, between polymorphi... more Evidence for linkage has been sought, in four pedigrees with Crouzon syndrome, between polymorphic markers known to be linked to the Saethre-Chotzen locus on 7p and another form of autosomal dominant craniosynostosis on 5q. The data we present exclude Crouzon syndrome as an allelic variant at either of these known craniosynostosis loci.

Research paper thumbnail of Cerebellar ataxia and ectodermal dysplasia in brothers

Journal of Medical Genetics, Jun 1, 1993

Two brothers are documented with an ectodermal dysplasia primarily involving the teeth and hair. ... more Two brothers are documented with an ectodermal dysplasia primarily involving the teeth and hair. Both have developed cerebellar ataxia in the early teens. (J Med Genet 1993;30:515-17) The association of a cerebellar ataxia and an ectodermal dysplasia is unusual, and has only been reported in seven patients.'-3 Ectodermal features have generally been confined to hair and teeth with the cerebellar ataxia being later in onset and progressive in nature. The main additional clinical features have varied from one report to another and have included mental retardation, short stature, deafness, and hypogonadism. We now report a further sibship with this rare entity but with normal intelligence, and review this group of conditions.

Research paper thumbnail of The 12q14 microdeletion syndrome: Additional patients and further evidence that HMGA2 is an important genetic determinant for human height

European Journal of Medical Genetics, Apr 1, 2009

Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to ... more Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to thrive, short stature, learning disabilities and Buschke-Ollendorff lesions in bone and skin. This report on two additional patients with this microdeletion syndrome emphasizes the rather constant and uniform phenotype encountered in this disorder and refines the critical region to a 2.61 Mb interval on 12q14.3, encompassing 10 RefSeq genes. We have previously shown that LEMD3 haploinsufficiency is responsible for the Buschke-Ollendorff lesions and now provide strong evidence that a heterozygous deletion of HMGA2 is causing the growth failure observed in this disorder. The identification of an intragenic HMGA2 deletion in a boy with proportionate short stature and the cosegregation of this deletion with reduced adult height in the extended family of the boy further underscore the role of HMGA2 in regulating human linear growth.

Research paper thumbnail of Evidence for locus heterogeneity in acrocephalosyndactyly: A refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p-and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p and 5q

Amer J Hum Genet, 1994

Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous gro... more Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous group of disorders, frequently involving digital abnormalities. We have previously provisionally assigned the gene for one such condition, Saethre-Chotzen syndrome (ACS III), to chromosome 7p. Linkage analysis is now reported between ACS III and dinucleotide repeat loci on distal 7p. The maximum lod scores, Zmax, were 5.57 at a recombination fraction of .05, with D7S488, and 4.74 at a recombination fraction of .05, with D7S493. Only weak linkage, not reaching significance, was found with distal markers (D7S513 and afm281vc9) and a proximal marker (D7S516). Multipoint analysis shows that the disease locus lies between D7S513 and D7S516. Analysis of individual recombinants shows that the most likely position is between D7S493 and D7S516. Linkage data in regard of Jackson-Weiss syndrome demonstrate that this autosomal dominant form of acrocephalosyndactyly does not map to the ACS III region on 7p or to the acrocephalosyndactyly locus on 5q (Boston type). These findings underline the genetic heterogeneity among the different clinical conditions manifesting with acrocephalosyndactyly.

Research paper thumbnail of Moebius sequence and hypogonadotrophic hypogonadism

American journal of medical genetics. Part A, Jan 15, 2003

A distinct form of Moebius sequence is associated with hypogonadotrophic hypogonadism. There have... more A distinct form of Moebius sequence is associated with hypogonadotrophic hypogonadism. There have been five such cases to date. We now add a further case with detailed neurologic, endocrine, and autopsy findings and offer a hypothesis drawing parallels with the already established basis of hypogonadotrophic hypogonadism in the X-linked form of Kallman syndrome.

Research paper thumbnail of Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis

Nature genetics, 1999

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the tr... more The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. T...

Research paper thumbnail of A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis

Nature genetics, 1998

Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal domin... more Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal dominant trait; association with anterior meningocoele, presacral teratoma and anorectal abnormalities constitutes the Currarino triad (MIM 176450). Malformation at the caudal end of the developing notochord at approximately Carnegie stage 7 (16 post-ovulatory days), which results in aberrant secondary neurulation, can explain the observed pattern of anomalies. We previously reported linkage to 7q36 markers in two dominantly inherited sacral agenesis families. We now present data refining the initial subchromosomal localization in several additional hereditary sacral agenesis (HSA) families. We excluded several candidate genes before identifying patient-specific mutations in a homeobox gene, HLXB9, which was previously reported to map to 1q41-q42.1 and to be expressed in lymphoid and pancreatic tissues.

Research paper thumbnail of Evidence for locus heterogeneity in acrocephalosyndactyly: a refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p--and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p and 5q

American journal of human genetics, 1994

Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous gro... more Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous group of disorders, frequently involving digital abnormalities. We have previously provisionally assigned the gene for one such condition, Saethre-Chotzen syndrome (ACS III), to chromosome 7p. Linkage analysis is now reported between ACS III and dinucleotide repeat loci on distal 7p. The maximum lod scores, Zmax, were 5.57 at a recombination fraction of .05, with D7S488, and 4.74 at a recombination fraction of .05, with D7S493. Only weak linkage, not reaching significance, was found with distal markers (D7S513 and afm281vc9) and a proximal marker (D7S516). Multipoint analysis shows that the disease locus lies between D7S513 and D7S516. Analysis of individual recombinants shows that the most likely position is between D7S493 and D7S516. Linkage data in regard of Jackson-Weiss syndrome demonstrate that this autosomal dominant form of acrocephalosyndactyly does not map to the ACS III region on...

Research paper thumbnail of Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis

Research paper thumbnail of Update on Kleefstra syndrome

Molecular Syndromology, 2012

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual dis... more Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

Research paper thumbnail of Enlarged vestibular aqueduct: a radiological marker of Pendred syndrome, and mutation of the PDS gene

QJM, 2000

Although the textbook view of Pendred syndrome is that of an autosomal recessive condition charac... more Although the textbook view of Pendred syndrome is that of an autosomal recessive condition characterized by deafness and goitre, it is increasingly clear that not all such patients present this classical clinical picture. Malformations of the inner ear, specifically enlargement of the vestibular aqueduct, are common in Pendred syndrome and mutations in the PDS (Pendred Syndrome) gene have been recorded in patients presenting with deafness and vestibular aqueduct dilatation only, without other features of Pendred syndrome. Since this is the most common radiological malformation of the cochlea in deaf patients, we investigated what proportion of such cases were due to mutation of the PDS gene. We assessed 57 patients referred with radiological evidence of vestibular aqueduct enlargement, by history, clinical examination, perchlorate discharge test and molecular analysis of the PDS locus. Forty-one patients (72%) had unequivocal evidence of Pendred syndrome. The finding of a single heterozygous mutation at the PDS gene in a further eight was strongly suggestive of a critical role for pendrin, the protein product of the PDS gene, in the generation of enlarged vestibular aqueducts in at least 86% (49/57 cases) of patients with this radiological malformation. Securing the diagnosis of Pendred syndrome may be difficult, especially in the single case. Goitre is an inconstant finding, and the perchlorate discharge test, although helpful, is of diagnostic value only if abnormal. Enlargement of the vestibular aqueduct should be considered as the most likely presentation of Pendred syndrome and should prompt specific investigation of that diagnostic possibility. Pendred syndrome might henceforth be recharacterized as deafness with enlargement of the vestibular aqueduct, which is sometimes associated with goitre.

Research paper thumbnail of Symptomatic anal anomalies in chromosome 22q11 deletion syndrome: a report of three patients

Pediatric Surgery International, 2006

Deletion of chromosome 22q11 is a common genetic condition with varying clinical presentation ran... more Deletion of chromosome 22q11 is a common genetic condition with varying clinical presentation ranging from neonatal fatality to patients whose presentation to medical services will be prompted after a few years by speech delay or mild developmental concerns. While most published data relating to patients with 22q11 deletions has focused on the ''classical'' presentation of the condition with cardiac manifestations, hypocalcaemia and velopharyngeal insufficiency, a much wider range of clinical presentations can characterise this syndrome. Anal anomalies, comprising imperforate anus and symptomatic anal stenosis, are a rarely described presentation of this multisystem disorder. In this report we document three patients presenting to paediatric services with symptoms attributed initially to symptomatic anal stenosis/atresia.

Research paper thumbnail of Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes

New England Journal of Medicine, 2008

BACKGROUND-Duplications and deletions in the human genome can cause disease or predispose persons... more BACKGROUND-Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.

Research paper thumbnail of X-linked deafness, stapes gushers and a distinctive defect of the inner ear

Neuroradiology, 1991

The association of X-linked mixed deafness with stapes gusher has been recognised for 20 years, m... more The association of X-linked mixed deafness with stapes gusher has been recognised for 20 years, mad imaging studies by polytomography have shown dilatation of the lateral end of the internal auditory meatus (IAM) in some cases. We have made genetic linkage studies in 7 pedigrees in whom deafness was inherited in an X-linked manner. All patients had a full range of audiometric and vestibular function tests. Thin section high resolution CT in two planes was used to assess the state of the middle and inner ears. We found a distinctive inner ear deformity in some of the deaf males characterised not only by a wide bulbous IAM but more importantly, by deficient or absent bone between the lateral end of the IAM and the basal turn of the cochlea. We believe that this results in a communication between the subarachnoid space in the IAM and the perilymph in the cochlea, leading to perilymphatic hydrops and a "gusher" if the stapes is disturbed. Moreover, some of the obligate female carriers seem to have a milder form of the same anomaly associated with slight hearing loss. Genetic studies on some of the deaf males with apparently normal inner ear anatomy suggest a different locus on the X chromosome and hence a different pathogenesis for the deafness.

Research paper thumbnail of Disordered Peripheral Nerve Conduction in DOOR(S) Syndrome

Neuropediatrics, 1994

A case of DOOR(S) syndrome is detailed and the neurophysiological abnormalities observed in this ... more A case of DOOR(S) syndrome is detailed and the neurophysiological abnormalities observed in this patient and in other cases with this rare but recognisable autosomal recessive condition are considered. Particular emphasis is paid to the abnormal peripheral nerve conduction, which has not previously been recorded in the condition.

Research paper thumbnail of Mutations in CDMP1 cause autosomal dominant brachydactyly type C

Research paper thumbnail of Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis

Journal of Medical Genetics, 2008

Patients with a microscopically visible deletion of the distal part of the long arm of chromosome... more Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects, as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. To describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and to report on the molecular characterisation of the deletion size. The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in 10 of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalities to a 360 kb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.

Research paper thumbnail of Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases

Journal of Medical Genetics, 2005

Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated... more Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. Methods: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. Results: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. Conclusions: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

Research paper thumbnail of Fluorescent in situ hybridisation (FISH) for hemizygous deletion at the elastin locus in patients with isolated supravalvular aortic stenosis

Journal of Medical Genetics, 1997

Both Williams syndrome and isolated supravalvular aortic stenosis (SVAS) are caused by mutations ... more Both Williams syndrome and isolated supravalvular aortic stenosis (SVAS) are caused by mutations at the elastin locus. Deletion demonstrable by FISH is the hallmark of Williams syndrome, whereas the mutations reported so far in SVAS have been more subtle. FISH positive elastin hemizygosity has not been reported in isolated SVAS. This report records our experience of FISH for elastin deletion in isolated SVAS and specifically reports a patient with non-Williams related SVAS, positive for the elastin deletion by FISH.

Research paper thumbnail of Close linkage of a gene for X linked deafness to three microsatellite repeats at Xq21 in radiologically normal and abnormal families

Journal of Medical Genetics, 1994

We have used three highly polymorphic microsatellite repeats from Xq21 to type families in whom a... more We have used three highly polymorphic microsatellite repeats from Xq21 to type families in whom a gene for X linked deafness with perilymphatic gusher (DFN 3) was segregating. All three markers were tightly linked to the disease in its radiologically normal and abnormal forms, with a maximum lod score of 10.37 with DXS995 and 8.44 with DXS986 at zero recombination, and 14.03 with DXS1002 at theta = 0.01. In an isolated case of deafness of this type, DXS995 indicated either the first recombination observed between the marker and the disease gene or a new mutation in the proband. Southern blotting using a cosmid fragment from the candidate region has confirmed a de novo mutation by showing a deletion in the proband which is not present in his mother as judged by dosage analysis. We also describe a family with a paracentric inversion associated with a microdeletion and discuss how deletion mapping using these and other markers in the region has helped to define a candidate region for the gene.

Research paper thumbnail of Crouzon syndrome is not linked to craniosynostosis loci at 7p and 5qter

Journal of Medical Genetics, 1994

Evidence for linkage has been sought, in four pedigrees with Crouzon syndrome, between polymorphi... more Evidence for linkage has been sought, in four pedigrees with Crouzon syndrome, between polymorphic markers known to be linked to the Saethre-Chotzen locus on 7p and another form of autosomal dominant craniosynostosis on 5q. The data we present exclude Crouzon syndrome as an allelic variant at either of these known craniosynostosis loci.