RESUMEN
Isolated congenital anosmia (ICA) is a rare disorder, where otherwise healthy individuals present with an inability to smell since birth. A list of studies have described the genes involved in syndromic anosmia; however, the genetics of ICA is still in its infancy. Studies in mice show that the cyclic nucleotide-gated channel subunit CNGA2, expressed in the olfactory epithelium has a crucial role in olfactory signal transduction. We have identified a novel X-linked stop mutation in CNGA2 (c.634C>T, p.R212*) in two brothers with ICA using exome sequencing. No additional mutations in CNGA2 were identified in a cohort of 31 non-related ICA individuals. Magnetic resonance brain imaging revealed diminished olfactory bulbs and flattened olfactory sulci. This is the first report of a mutation in the cyclic nucleotide-gated gene CNGA2 and supports the critical role of this gene in human olfaction.
Asunto(s)
Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Mutación , Trastornos del Olfato/congénito , Adulto , Secuencia de Aminoácidos , Canales Catiónicos Regulados por Nucleótidos Cíclicos/química , Análisis Mutacional de ADN , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Trastornos del Olfato/diagnóstico , Trastornos del Olfato/genética , Bulbo Olfatorio/patología , Linaje , Alineación de Secuencia , HermanosRESUMEN
Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1, RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.
Asunto(s)
Anomalías Múltiples/genética , Blefaroptosis/congénito , Duplicación Cromosómica , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Adulto , Animales , Blefaroptosis/genética , Estatura/genética , Niño , Fisura del Paladar/genética , Femenino , Dedos/anomalías , Humanos , Discapacidad Intelectual/genética , Cariotipificación , Masculino , Ratones , Ratones Transgénicos , Microcefalia/genética , SíndromeRESUMEN
Autosomal recessive primary microcephaly (MCPH) is caused by mutations in at least eight different genes involved either in cell division or DNA repair. Most mutations are identified in consanguine families from Pakistan, Iran and India. To further assess their genetic heterogeneity and mutational spectra, we have analyzed 57 consanguine Pakistani MCPH families. In 34 MCPH families, we detected linkage to five out of the eight well-characterized disease loci and identified mutations in 27 families, leaving seven families without mutations in the coding exons of the presumably underlying MCPH genes. In the MCPH cohort 23 families could not be linked to any of the known loci, pointing to remarkable locus heterogeneity. The majority of mutations were found in ASPM followed by WDR62, CENPJ, CEP152 and MCPH1. One ASPM mutation (p.Trp1326*) was found in as many as eight families suggesting a Pakistani founder mutation. One third of the families were linked to ASPM followed by WDR62 confirming previous data. We identified three novel ASPM mutations, four novel WDR62 mutations, one novel MCPH1 mutation and two novel CEP152 mutations. CEP152 mutations have not been described before in the Pakistani population.
Asunto(s)
Heterogeneidad Genética , Microcefalia/genética , Proteínas de Ciclo Celular/genética , Consanguinidad , Proteínas del Citoesqueleto , Familia , Orden Génico , Genes Recesivos , Ligamiento Genético , Sitios Genéticos , Humanos , Mutación , Proteínas del Tejido Nervioso/genética , PakistánRESUMEN
Congenital anterior midline cervical cleft (CAMCC) is a rare anomaly, with less than 100 cases reported. The cause of CAMCC is unknown, but genetic factors must be considered as part of the etiology. Three cases of CAMCC are presented. This is the first genetic study of isolated CAMCC. Conventional cytogenetics, array-comparative genomic hybridization (CGH) and whole exome sequencing were performed, including a search of relevant syndromes in the Online Mendelian Inheritance in Man (OMIM) database. Array CGH indicated a loss of the PAPPA gene in one of the patients, while exome sequencing showed a mutation in SIX5 in another patient. Both aberrations were inherited from unaffected parents. These results most likely imply that the identified mutations are not disease-causing, although they may be contributing factors if CAMCC has a polygenic inheritance.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Hibridación Genómica Comparativa , Femenino , Humanos , Lactante , MasculinoRESUMEN
Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.
Asunto(s)
Anomalías Múltiples/genética , Agenesia del Cuerpo Calloso/genética , Trastorno Autístico/genética , Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Trastornos del Habla/genética , Factores de Transcripción/genética , Adulto , Preescolar , Haploinsuficiencia , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Loss of smell (anosmia) is common in the general population and the frequency increases with age. A much smaller group have no memory of ever being able to smell and are classified as having isolated congenital anosmia (ICA). Families are rare, and tend to present in a dominant inheritance pattern. Despite a strong degree of heritability, no human disease-causing mutations have been identified. Anosmia is part of the clinical spectrum in various diseases, as seen in Kallmann syndrome, various ciliopathies and congenital insensitivity to pain. This review will focus on ICA through already published families and cases as well as syndromes where anosmia is part of the clinical disease spectrum. Furthermore, olfactory signal transduction pathway genes and animal models may shed light on potential candidate genes and pathways involved in ICA.
Asunto(s)
Trastornos del Olfato/genética , Humanos , Trastornos del Olfato/complicaciones , Trastornos del Olfato/congénito , Trastornos del Olfato/etiología , Insensibilidad Congénita al Dolor/complicaciones , Insensibilidad Congénita al Dolor/genética , Transducción de Señal/genética , Olfato/fisiología , SíndromeRESUMEN
Genetic variants, including single-nucleotide polymorphisms (SNPs), are key determiners of interindividual differences in treatment efficacy and toxicity in childhood acute lymphoblastic leukemia (ALL). Although up to 13 chemotherapeutic agents are used in the treatment of this cancer, it remains a model disease for exploring the impact of genetic variation due to well-characterized cytogenetics, drug response pathways and precise monitoring of minimal residual disease. Here, we have selected clinically relevant genes and SNPs through literature screening, and on the basis of associations with key pathways, protein-protein interactions or downstream partners that have a role in drug disposition and treatment efficacy in childhood ALL. This allows exploration of pathways, where one of several genetic variants may lead to similar clinical phenotypes through related molecular mechanisms. We have designed a cost-effective, high-throughput capture assay of â¼25,000 clinically relevant SNPs, and demonstrated that multiple samples can be tagged and pooled before genome capture in targeted enrichment with a sufficient sequencing depth for genotyping. This multiplexed, targeted sequencing method allows exploration of the impact of pharmacogenetics on efficacy and toxicity in childhood ALL treatment, which will be of importance for personalized chemotherapy.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Preescolar , Análisis Costo-Beneficio , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/economía , Humanos , Lactante , Recién Nacido , Farmacogenética , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Resultado del TratamientoRESUMEN
Inflammatory bowel disease (IBD) is a multifactorial disorder with an unknown aetiology. The aim of this study is to employ a murine model of IBD to identify pathways and genes, which may play a key role in the pathogenesis of IBD and could be important for discovery of new disease markers in human disease. Here, we have investigated severe combined immunodeficient (SCID) mice, which upon adoptive transfer with concanavalin A-activated CD4(+) T cells develop inflammation of the colon with predominance in rectum. Mice with increasing level of inflammation was studied. RNA from rectum of transplanted and non-transplanted SCID mice was investigated by a genome-wide gene expression analysis using the Affymetrix mouse expression array 430A (MOE430A) including 22,626 probe sets. A significant change in gene expression (P = 0.00001) is observed in 152 of the genes between the non-transplanted control mice and colitis mice, and among these genes there is an overrepresentation of genes involved in inflammatory processes. Some of the most significant genes showing higher expression encode S100A proteins and chemokines involved in trafficking of leucocytes in inflammatory areas. Classification by gene clustering based on the genes with the significantly altered gene expression corresponds to two different levels of inflammation as established by the histological scoring of the inflamed rectum. These data demonstrate that this SCID T-cell transfer model is a useful animal model for human IBD and can be used for suggesting candidate genes involved in the pathogenesis and for identifying new molecular markers of chronic inflammation in human IBD.
Asunto(s)
Colitis/genética , Perfilación de la Expresión Génica/métodos , Genoma , Linfocitos T/inmunología , Traslado Adoptivo/efectos adversos , Animales , Mapeo Cromosómico , Análisis por Conglomerados , Colitis/etiología , Colitis/inmunología , Colon/metabolismo , Colon/patología , Concanavalina A/inmunología , Femenino , Genoma Humano , Humanos , Enfermedades Inflamatorias del Intestino/genética , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sintenía , Linfocitos T/trasplanteRESUMEN
Despite the rapidly increasing number of sequenced and re-sequenced genomes, many issues regarding the computational assembly of large-scale sequencing data have remain unresolved. Computational assembly is crucial in large genome projects as well for the evolving high-throughput technologies and plays an important role in processing the information generated by these methods. Here, we provide a comprehensive overview of the current publicly available sequence assembly programs. We describe the basic principles of computational assembly along with the main concerns, such as repetitive sequences in genomic DNA, highly expressed genes and alternative transcripts in EST sequences. We summarize existing comparisons of different assemblers and provide a detailed descriptions and directions for download of assembly programs at: http://genome.ku.dk/resources/assembly/methods.html.
Asunto(s)
Genómica/métodos , Biología Computacional/métodos , ADN/química , Etiquetas de Secuencia Expresada , Genoma , Polimorfismo de Nucleótido Simple , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
BACKGROUND: Congenital heart disease (CHD) is the most common birth defect and affects nearly 1% of newborns. The aetiology of CHD is largely unknown and only a small percentage can be assigned to environmental risk factors such as maternal diseases or exposure to mutagenic agents during pregnancy. Chromosomal imbalances have been identified in many forms of syndromic CHD, but very little is known about the impact of DNA copy number changes in non-syndromic CHD. METHOD: A sub-megabase resolution array comparative genome hybridisation (CGH) screen was carried out on 105 patients with CHD as the sole abnormality at the time of diagnosis. RESULTS: There were 18 chromosomal changes detected, which do not coincide with common DNA copy number variants, including one de novo deletion, two de novo duplications and eight familial copy number variations (one deletion and seven duplications). CONCLUSIONS: Our data show that submicroscopic deletions and duplications play an important role in the aetiology of this condition, either as direct causes or as genetic risk factors for CHD. These findings have immediate consequences for genetic counselling and should pave the way for the elucidation of the pathogenetic mechanisms underlying CHD.
Asunto(s)
Aberraciones Cromosómicas/estadística & datos numéricos , Hibridación Genómica Comparativa/métodos , Cardiopatías Congénitas/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Niño , Deleción Cromosómica , Análisis Citogenético , Femenino , Dosificación de Gen , Duplicación de Gen , Genoma Humano , Humanos , Lactante , Recién Nacido , Masculino , FenotipoAsunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Discapacidades del Desarrollo/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Niño , Preescolar , Bandeo Cromosómico , Cromosomas Humanos Par 20/genética , Femenino , Duplicación de Gen , Humanos , Masculino , SíndromeRESUMEN
Mowat-Wilson syndrome (MWS) is an autosomal dominant developmental disorder with mental retardation and variable multiple congenital abnormalities due to mutations of the ZEB2 (ZFHX1B) gene at 2q22. MWS was first described in 1998 and the causative gene was delineated in 2001. Since then, 115 different mutations of ZEB2 have been published in association with this syndrome in 161 individuals. However, recent reports suggest that due to the variability of the congenital abnormalities, this syndrome may still be underdiagnosed. We report two unrelated patients with MWS where the clinical diagnosis was established only after finding of disruption of the ZEB2 gene by a balanced translocation breakpoint and an interstitial microdeletion, respectively.
Asunto(s)
Anomalías Múltiples/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Anomalías Múltiples/diagnóstico , Rotura Cromosómica , Análisis Citogenético , Femenino , Humanos , Recién Nacido , Discapacidad Intelectual/diagnóstico , Síndrome , Caja Homeótica 2 de Unión a E-Box con Dedos de ZincRESUMEN
In this study we report a female patient with an interstitial duplication of a region (10q22-q23) which is rarely reported in the literature. We fine mapped the aberration with array CGH, which revealed an 18.6-Mb duplication, covering 89 annotated genes, at 10q22.2-q23.33. There were no other deletions or duplications elsewhere in the genome. The main clinical features of the patient are microcephaly and congenital heart disease, which are likely to be caused by dosage effect of one or several genes in the duplicated region. Similar phenotypes have been found in other patients with 10q11-q22 duplications and in two out of three patients with 10q22-q25 duplications. However, most of the duplication cases were investigated only by conventional chromosome analyses, and fine mapping of these and other duplications of 10q22-q23 are warranted for genotype-phenotype comparisons.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 10/genética , Genes Duplicados , Cardiopatías Congénitas/genética , Microcefalia/genética , Preescolar , Femenino , HumanosRESUMEN
In this study, we present a 38-year-old woman with an interstitial deletion of 4p15.1-15.3, mild mental retardation, epilepsy and polymicrogyria adjacent to an arachnoid cyst of the left temporal lobe. The deletion was ascertained through array-comparative genome hybridization screening of patients with epilepsy and brain malformations. To date, about 35 patients with cytogenetically visible deletions involving 4p15 and without Wolf-Hirschhorn syndrome have been described, but the extent of the deletions has not been determined in the majority of these cases. The clinical manifestations of the patient described in this study were similar but not identical to the previously reported cases with 4p15 interstitial deletions. This finding indicates the presence of one or more genes involved in brain development and epilepsy in this chromosome region.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Malformaciones del Desarrollo Cortical/genética , Lóbulo Temporal/anomalías , Adulto , Femenino , HumanosRESUMEN
Axenfeld-Rieger syndrome (ARS) is a genetically heterogeneous autosomal dominant disorder mainly characterized by developmental defects of the anterior segment and extraocular anomalies. ARS shows great clinical variability and encompasses several conditions with overlapping phenotypes, including Rieger syndrome (RS). RS is characterized by developmental defects of the eyes, teeth and umbilicus, and the main causative gene is PITX2 (paired-like homeodomain transcription factor 2, or RIEG1) at 4q25. PITX2 mutations show great variety, from point mutations to microscopic or submicroscopic deletions, and apparently balanced translocations in few cases. We identified cytogenetically undetectable submicroscopic deletions at 4q25 in two unrelated patients diagnosed with RS. One patient had a t(4;17)(q25;q22)dn translocation with a deletion at the 4q breakpoint, and the other patient had an interstitial deletion of 4q25. Both deletions included only the PITX2 and ENPEP (glutamyl aminopeptidase) genes.
Asunto(s)
Análisis Citogenético , Anomalías del Ojo/genética , Eliminación de Gen , Proteínas de Homeodominio/genética , Anomalías Dentarias/genética , Factores de Transcripción/genética , Preescolar , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 4 , Glutamil Aminopeptidasa/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Síndrome , Translocación Genética , Proteína del Homeodomínio PITX2RESUMEN
In order to identify novel genes involved in early meiosis and early ovarian development in the mouse, we used microarray technology to compare transcriptional activity in ovaries without meiotic germ cells at embryonic age 11.5 (E11.5) and E13.5 ovaries with meiosis. Overall, 182 genes were differentially expressed; 134 were known genes and 48 were functionally uncharacterized. A comparison of our data with the literature associated, for the first time, at least eight of the known genes with female meiosis/germ cell differentiation (Aldh1a1, C2pa, Tex12, Stk31, Lig3, Id4, Recql, Piwil2). These genes had previously only been described in spermatogenesis. The microarray also detected an abundance of vesicle-related genes of which four were upregulated (Syngr2, Stxbp1, Ric-8, SytIX) and one (Myo1c) was downregulated in E13.5 ovaries. Detailed analysis showed that the temporal expression of SytIX also coincided with the first meiotic wave in the pubertal testis. This is the first time that SytIX has been reported in non-neuronal tissue. Finally, we examined the expression of one of the uncharacterized genes and found it to be gonad-specific in adulthood. We named this novel transcript "Gonad-expressed transcript 1" (Get-1). In situ hybridization showed that Get-1 was expressed in meiotic germ cells in both fetal ovaries and mature testis. Get-1 is therefore a novel gene in both male and female meiosis.
Asunto(s)
Feto/metabolismo , Perfilación de la Expresión Génica , Meiosis/genética , Ovario/embriología , Ovario/metabolismo , Testículo/embriología , Testículo/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Encéfalo/embriología , Encéfalo/metabolismo , ADN Complementario/genética , Regulación hacia Abajo/genética , Femenino , Masculino , Ratones , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Especificidad de Órganos/genética , Ovario/citología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Testículo/citología , Transcripción Genética , Regulación hacia Arriba/genéticaRESUMEN
We report a familial cryptic reciprocal translocation between 4q35 and 10p15 leading to deletion of the terminal long arm of chromosome 4 and duplication of the terminal short arm of chromosome 10 in two family members who both have immunological disturbances and a similar facial appearance. The precise location and extent of the deletion and duplication was determined by fluorescence in situ hybridization (FISH). Furthermore, we investigated the deletion breakpoint of a previously reported patient with 4q34.3-qter deletion [Van Buggenhout et al. (2004); Am J Med Genet Part A 131A:186-189].
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 4/genética , Síndromes de Inmunodeficiencia/genética , Discapacidad Intelectual/genética , Fenotipo , Translocación Genética/genética , Anomalías Múltiples/patología , Adolescente , Adulto , Femenino , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/patología , LinajeRESUMEN
BACKGROUND: Characterisation of disease associated balanced chromosome rearrangements is a promising starting point in the search for candidate genes and regulatory elements. METHODS: We have identified and investigated three patients with limb abnormalities and breakpoints involving chromosome 2q31. Patient 1 with severe brachydactyly and syndactyly, mental retardation, hypoplasia of the cerebellum, scoliosis, and ectopic anus, carries a balanced t(2;10)(q31.1;q26.3) translocation. Patient 2, with translocation t(2;10)(q31.1;q23.33), has aplasia of the ulna, shortening of the radius, finger anomalies, and scoliosis. Patient 3 carries a pericentric inversion of chromosome 2, inv(2)(p15q31). Her phenotype is characterised by bilateral aplasia of the fibula and the radius, bilateral hypoplasia of the ulna, unossified carpal bones, and hypoplasia and dislocation of both tibiae. RESULTS: By fluorescence in situ hybridisation, we have mapped the breakpoints to intervals of approximately 170 kb or less. None of the three 2q31 breakpoints, which all mapped close to the HOXD cluster, disrupted any known genes. CONCLUSIONS: Hoxd gene expression in the mouse is regulated by cis-acting DNA elements acting over distances of several hundred kilobases. Moreover, Hoxd genes play an established role in bone development. It is therefore very likely that the three rearrangements disturb normal HOXD gene regulation by position effects.
Asunto(s)
Rotura Cromosómica/genética , Proteínas de Homeodominio/genética , Deformidades Congénitas de las Extremidades/genética , Familia de Multigenes/genética , Adolescente , Adulto , Mapeo Cromosómico , Cromosomas Humanos Par 2/genética , Biología Computacional , Femenino , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipificación , Masculino , Mutación/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Brachydactyly type A2 (OMIM 112600) is characterised by hypoplasia/aplasia of the second middle phalanx of the index finger and sometimes the little finger. BDA2 was first described by Mohr and Wriedt in a large Danish/Norwegian kindred and mutations in BMPR1B were recently demonstrated in two affected families. METHODS: We found and reviewed Mohr and Wriedt's original unpublished annotations, updated the family pedigree, and examined 37 family members clinically, and radiologically by constructing the metacarpo-phalangeal profile (MCPP) pattern in nine affected subjects. Molecular analyses included sequencing of BMPR1B, linkage analysis for STS markers flanking GDF5, sequencing of GDF5, confirmation of the mutation by a restriction enzyme assay, and localisation of the mutation inferred from the very recently reported GDF5 crystal structure, and by superimposing the GDF5 protein sequence onto the crystal structure of BMP2 bound to Bmpr1a. RESULTS: A short middle phalanx of the index finger was found in all affected individuals, but other fingers were occasionally involved. The fourth finger was characteristically spared. This distinguishes Mohr-Wriedt type BDA2 from BDA2 caused by mutations in BMPR1B. An MCPP analysis most efficiently detected mutation carrier status. We identified a missense mutation, c.1322T>C, causing substitution of a leucine with a proline at amino acid residue 441 within the active signalling domain of GDF5. The mutation was predicted to reside in the binding site for BMP type 1 receptors. CONCLUSION: GDF5 is a novel BDA2 causing gene. It is suggested that impaired activity of BMPR1B is the molecular mechanism responsible for the BDA2 phenotype.