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PubMed2004

A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1.

Cell adhesion to extracellular matrix (ECM) proteins is crucial for the structural integrity of tissues and epithelial-mesenchymal interactions mediating organ morphogenesis. Here we describe how the loss of a cytoplasmic multi-PDZ scaffolding protein, glutamate receptor interacting protein 1 (GRIP1), leads to the formation of subepidermal hemorrhagic blisters, renal agenesis, syndactyly or polydactyly and permanent fusion of eyelids (cryptophthalmos). Similar malformations are characteristic of individuals with Fraser syndrome and animal models of this human genetic disorder, such as mice carrying the blebbed mutation (bl) in the gene encoding the Fras1 ECM protein. GRIP1 can physically interact with Fras1 and is required for the localization of Fras1 to the basal side of cells. In one animal model of Fraser syndrome, the eye-blebs (eb) mouse, Grip1 is disrupted by a deletion of two coding exons. Our data indicate that GRIP1 is required for normal cell-matrix interactions during early embryonic development and that inactivation of Grip1 causes Fraser syndrome-like defects in mice.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome.

RAB, ADP-ribosylation factors (ARFs) and ARF-like (ARL) proteins belong to the Ras superfamily of small GTP-binding proteins and are essential for various membrane-associated intracellular trafficking processes. None of the approximately 50 known members of this family are linked to human disease. Using a bioinformatic screen for ciliary genes in combination with mutational analyses, we identified ARL6 as the gene underlying Bardet-Biedl syndrome type 3, a multisystemic disorder characterized by obesity, blindness, polydactyly, renal abnormalities and cognitive impairment. We uncovered four different homozygous substitutions in ARL6 in four unrelated families affected with Bardet-Biedl syndrome, two of which disrupt a threonine residue important for GTP binding and function of several related small GTP-binding proteins. Analysis of the Caenorhabditis elegans ARL6 homolog indicates that it is specifically expressed in ciliated cells, and that, in addition to the postulated cytoplasmic functions of ARL proteins, it undergoes intraflagellar transport. These findings implicate a small GTP-binding protein in ciliary transport and the pathogenesis of a pleiotropic disorder.

ADP-Ribosylation Factors↗
PubMed2006

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.

Abnormalities, Multiple↗
PubMed2006

MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome.

Meckel syndrome (MKS) is a severe fetal developmental disorder reported in most populations. The clinical hallmarks are occipital meningoencephalocele, cystic kidney dysplasia, fibrotic changes of the liver and polydactyly. Here we report the identification of a gene, MKS1, mutated in MKS families linked to 17q. Mks1 expression in mouse embryos, as determined by in situ hybridization, agrees well with the tissue phenotype of MKS. Comparative genomics and proteomics data implicate MKS1 in ciliary functions.

Abnormalities, Multiple↗
PubMed2026

Long-read sequencing reveals a hidden Alu-mediated splice defect in CPLANE1, causing orofaciodigital syndrome type VI.

Orofaciodigital syndrome type VI (OFD VI) is a recessive ciliopathy characterized by excessive polydactyly, molar tooth sign, cleft lip, and developmental delay, caused by pathogenic variants in CPLANE1. Here, we present a patient with OFD VI that remained genetically unexplained after routine genetic testing, including short-read whole genome sequencing (WGS). Using long-read sequencing, we found two biallelic splice-site variants in CPLANE1, c.8633-4_8633-3del, and an Alu element insertion close to an exon-intron boundary. Transcript analysis showed that each variant independently resulted in exon skipping, and quantitative expression studies revealed reduced total CPLANE1 mRNA levels in patient-derived fibroblasts. Based on these findings, we were able to re-classify the c.8633-4_8633-3del variant from a variant of uncertain significance (VUS) to likely pathogenic. The identification of an Alu element insertion missed by short-read WGS highlights the added diagnostic value of long-read sequencing in uncovering cryptic, transposable element-associated pathogenic variants.

Journal Article↗
PubMed1991

Quadriparesis in the Laurence-Moon-Biedl-Bardet syndrome: case report.

A 36 year old patient known to suffer from the Laurence-Moon-Biedl-Bardet syndrome (LMBBS) developed spastic quadriparesis. The typical features of the syndrome, presented by this patient were polydactyly, obesity, hypogonadism, retinitis pigmentosa and relative mental retardation. Severe spinal cervical and lumbar canal stenosis imaged by plain X-rays and computerised tomography was found. Magnetic resonance imaging showed significant atrophy of the spinal cord, indicating that the cause of the quadriparesis was cervical myelopathy. The patient underwent laminoplasty with some improvement.

Adult↗
PubMed2005

Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl syndrome family cohort.

The phenotype of Bardet-Biedl syndrome (BBS) is defined by the association of retinitis pigmentosa, obesity, polydactyly, hypogenitalism, renal disease and cognitive impairement. The significant genetic heterogeneity of this condition is supported by the identification, to date, of eight genes (BBS1-8) implied with cilia assembly or function. Triallelic inheritance has recently been suggested on the basis of the identification of three mutated alleles in two different genes for the same patient. In a cohort of 27 families, six BBS genes (namely BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8) have been studied. Mutations were identified in 14 families. Two mutations within the same gene have been identified in seven families. BBS1 is most frequently implied with the common M390R substitution at the homozygous state (n=2), or associated with another mutation at BBS1 (n=3). Compound heterozygous mutations have been found in BBS2 (one family) and BBS6 (one family). In seven other families, only one heterozygous mutation has been identified (once in BBS1, twice for BBS2 and three times in BBS6). Although our study did not reveal any families with bona fide mutations in two BBS genes, consistent with a triallelic hypothesis, we have found an excess of heterozygous single mutations. This study underlines the genetic heterogeneity of the BBS and the involvement of possibly unidentified genes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

MORM syndrome (mental retardation, truncal obesity, retinal dystrophy and micropenis), a new autosomal recessive disorder, links to 9q34.

A consanguineous pedigree is described where 14 individuals are affected with a novel autosomal recessive disorder, which causes static moderate mental retardation, truncal obesity, a congenital nonprogressive retinal dystrophy and micropenis in males. We have tentatively named this condition MORM syndrome. It shows similarities to Bardet-Biedl syndrome and Cohen syndrome, but can be distinguished by clinical features; the age of onset and nonprogressive nature of the visual impairment, the lack of characteristic facies, skin or gingival infection, microcephaly, 'mottled retina', polydactyly and small penis without testicular anomalies. Furthermore, linkage to the known Bardet-Biedl (BBS1-8) and Cohen syndrome loci was excluded. Autozygosity mapping identified a single homozygous subtelomeric region shared by all affecteds on chromosome 9q34.3, with a maximum LOD score of 5.64. We believe this to be the first example of the identification of a subtelomeric recessive locus by autozygosity mapping.

Chromosome Mapping↗
PubMed2006

Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by variable obesity, pigmentary retinopathy, polydactyly, mental retardation, hypogonadism and renal failure. In order to identify novel BBS loci we undertook autozygosity mapping studies using high-density SNP microarrays in consanguineous kindreds. We mapped a BBS locus to a 10.1 Mb region at 12q15-q21.2 in a large Omani BBS family (peak lod score 8.3 at theta = 0.0 for marker D12S1722) that contained the recently described BBS10 locus. Mutation analysis of candidate genes within the target interval, including the BBS10 gene, revealed a homozygous frameshift mutation in FLJ23560 and mutations were also detected in four smaller consanguineous families with regions of autozygosity at 12q21.2. These findings (a) confirm a previous report that FLJ23560 (BBS10) mutations are a significant cause of BBS, and (b) further demonstrate the utility of high-density SNP array mapping in consanguineous families for the mapping and identification of recessive disease genes.

Adult↗
PubMed2001

Early prenatal sonographic diagnosis and follow-up of Jeune syndrome.

Jeune syndrome or asphyxiating thoracic dysplasia is an autosomal recessive osteochondrodysplasia. It is one of the six short-rib (polydactyly) syndromes. The disease has a wide spectrum of manifestations, ranging from a latent to a mild or lethal condition. We describe the prenatal sonographic diagnosis of Jeune syndrome at 14 weeks of gestation in a fetus at risk for this condition, and the development of the syndrome throughout the pregnancy.

Anthropometry↗
PubMed2003

Anaesthetic management in McKusick-Kaufman syndrome.

The cardinal features of McKusick-Kaufman syndrome (MKS) are polydactyly and hydrometrocolpos. Sometimes, this abdominopelvic mass may restrict pulmonary function and decrease the oxygenation of the newborn. We present a case of MKS and review the clinical features and appropriate anaesthetic management. A 45-day-old girl, weighing 4450 g, born at term, presented to our Paediatric Surgery Department with abdominal distention, diarrhoea and vomiting, which started on the 15th day of life. On physical examination, peripheral cyanosis, tachycardia and tachypnoea were found. A prominent mass was palpated in the lower abdomen. There was vaginal atresia and a sixth digit was found on her left foot. There was a large cystic mass extending from the pelvis to the level of L1 displacing the diaphragm, and bilateral hydroureteronephrosis were seen on plain abdominal X-ray, ultrasonography and computerized tomography. In the preanaesthetic assessment, the patient was evaluated for multiple congenital anomalies. Our management of anaesthesia, for a neonate with severe hydrometrocolpos compressing the diaphragm, consisted of gastric decompression and preoxygenation before tracheal intubation, routine and airway pressure monitoring, periodic analyses of blood gases and maintenance of anaesthesia with a low concentration of volatile agent, together with an opioid.

Abnormalities, Multiple↗
PubMed2002

Glucose screening during active labour for the detection of undiagnosed hyperglycaemia and newborn malformations in a population without prenatal care.

AIM: This prospective study was undertaken to look at the frequency of hyperglycaemia in pregnant women who were without health benefits and did not receive prenatal specialist care, and to examine the relationship between fetal complications and the prenatal care received. METHODS: The subjects consisted of 304 pregnant women, divided into two groups. Group I included 176 women who had inadequate prenatal care (73 women with irregular care, and 103 women without any specialist care.) with a mean of 1.1 visits to a specialist. Group II included 128 women who had regular prenatal care with a mean of 6.5 consultations per patient. RESULTS: There were no statistical differences between the two groups in relation to maternal age, obstetrical history and gestational weeks. The familial antecedent of diabetes was found in 30.1% of women in group I and 19.5% of women in group II (p < 0.05). Hyperglycaemia was found in 55 (31.2%) patients in group I and 4 (3.1%) patients in group II (p < 0.001) with mean blood glucose levels of 163 and 130 mg/dL respectively. Clinical characteristics of newborns show statistically significant increased abnormalities in 15.9% of babies whose mothers had inadequate prenatal care vs. 3.9% of babies whose mothers had regular prenatal care. The abnormalities seen were myelomeningocele, cleft lip and palate, oesophageal atresia, polydactyly, phocomelia and encephalocele. CONCLUSIONS: The frequency of hyperglycaemia in pregnant women with inadequate prenatal care was higher than in pregnant women with regular prenatal care. Additionally newborn abnormalities and complications occurred more frequently in babies of mothers with inadequate prenatal care. The benefits of prenatal care are evident and it is important to improve and start instituting new programmes and ways of making health information available to women in primary care clinics to educate the general population and stress the importance of regular visits to a prenatal care specialist.

Adolescent↗
PubMed2001

Prenatal diagnosis of Bardet-Biedl syndrome by targeted second-trimester sonography.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by mental retardation, obesity, retinal degeneration, polydactyly and syndactyly, diabetes mellitus, hypogenitalism, renal dysplasia and short stature. Definitive molecular diagnosis for BBS is not currently available and counseling of affected families is based on the 25% recurrence risk consistent with autosomal recessive inheritance. Our case presents the first successful use of second trimester targeted sonographic anatomy scanning to prospectively identify a fetus affected with BBS, and indicates that ultrasound can be of critical importance in providing precise as well as timely prenatal diagnosis for families at risk for this serious disorder.

Adult↗
PubMed2001

First trimester prenatal diagnosis of chondroectodermal dysplasia (Ellis-van Creveld syndrome) with ultrasound.

Chondroectodermal dysplasia (Ellis-van Creveld syndrome) is an autosomal recessive condition characterized by short-limb dwarfism, postaxial polydactyly, ectodermal defects, and congenital heart disease. This condition is most prevalent in the Amish population of Lancaster, Pennsylvania, USA, occurring in 1/5000 births and in 1/60,000 births in the general population. This report presents a case of ultrasonographic detection of chondroectodermal dysplasia at 12 weeks of gestation.

Adult↗
PubMedDate not supplied

[Bardet-Biedl syndrome: aspects of nephro-urology and human genetics].

Bardet-Biedl syndrome is a genetically heterogeneous autosomal recessive complex of features in which five gene loci have been described up to now. The diagnosis of this rare syndrome is based on the main manifestations hypogonadism, age-dependent increasing obesity and reduction of renal function, age-dependent progressive retinal degeneration with blindness as well as postaxial polydactyly and mental retardation. The life expectancy is short. Problems of early diagnostics, secondary hyperparathyroidism as well as surgical reconstruction of the genitals and kidney replacement therapy are discussed.

Adolescent↗
PubMed2004

Severe abnormalities of the pons in two infants with goldenhar syndrome.

We describe 2 cases of Goldenhar syndrome with severe abnormalities of the pons. The first case is a 10-month-old Caucasian female infant. At birth the girl showed polydactyly, labiopalatoschisis, right ear agenesis, left eye coloboma and vertebral anomalies. She also had marked hypotonia, severely reduced movements and respiratory and feeding abnormalities. She required gastrostomy at 5 months and tracheostomy at 7 months. Brain MRI scans showed moderate cerebellar hypoplasia and severe abnormalities of the pons with a congenital cleft. The child died at age 12 months. Case 2 is a Caucasian boy. Clinical signs and presentation were similar to case 1. The child also had severely reduced lacrimation, sweating, with thermoregulation abnormalities. He also underwent gastrostomy at 18 months. The child is now 3 years old and is able to sit only with support. Brain MRI was similar to case 1. The association of Goldenhar syndrome and pons abnormalities in 2 subjects suggests that this is more than a mere coincidence. Further studies and characterization of the genes involved in Goldenhar syndrome are needed to establish an adequate genotype-phenotype correlation.

Abnormalities, Multiple↗
PubMedDate not supplied

[Nation-wide registration of limb deficiencies in Germany].

AIM: A detailed registration of the frequency and the aetiology of limb deficiencies has been established for the first time in Germany. METHOD: According to the ESPED model (Documentation of rare paediatric diseases in Germany) we send out at an interval of three months a questionnaire for registration of live births, still births and their limb deficiencies to 1 073 gynaecological hospitals. In case of a positive response for a limb deficiency a second questionnaire is sent for details about pregnancy, birth and family. The limb defects are registered according to the ICD-10 classification and statistically analysed. RESULTS: Current acquisition period: 48 months (April 2000-April 2004). Total number of registered births: 1 070 541. Number of live births with limb deficiencies: 1 534 (0.14 %). Number of still births with limb deficiencies: 55 (1.7 %). Minor limb deficiencies such as polydactyly (22.4 %) are more frequent than major deficiencies of the tibia (1.0 %) or of the fibula (1.6 %). A familiar disposition is found in 9.7 %. A correlation to the profession of parents or their age (mother: 29, father: 33), or nicotine abuse could not be detected. The numbers of special features during pregnancy (amniocentesis in 3.3 %, oligohydramnion in 0.5 %, polyhydramnion in 0.3 %, etc.) and during delivery (relation between normal delivery and caesarean section = 59.5 %/29 %, etc.) were similar to the frequencies in the normal population. CONCLUSIONS: Our register represents the largest study world-wide in respect to the birth rate and the most accurate record of limb deficiencies. In the current acquisition period no correlation of the registered limb deficiencies to environmental effects, individual misbehaviour, exposed professional group and peculiarities during pregnancy and parturition could be found. The continuation of our register is essential for further detection of the incidence and aetiology of limb defects.

Abnormalities, Multiple↗
PubMed1992

[Prenatal diagnosis of thanatophoric dwarfism].

Thanatophoric dwarfism is a rare malformation, occurring in less than 1:10,000 pregnancies. It can be discovered by standard ultrasound examination, but other skeletal dysplasias such as achondroplasia, achondrogenesis and polydactyly syndromes must be taken into consideration. Sonographic findings are polyhydramnia, narrow chest, symmetric tetramicromelia and macrocephaly. Macrocephaly might cause a problem for vaginal delivery. The narrow chest with secondary lung hypoplasia determines the infaust prognosis.

Adult↗