Publications by authors named "Peter Meinecke"

39 Publications

Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities.

Am J Hum Genet 2020 12 6;107(6):1044-1061. Epub 2020 Nov 6.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address:

Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulfated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report bi-allelic pathogenic variants in HS2ST1 in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. The heparan sulfate synthesized by the individual 1 cell line lacks 2-O-sulfated domains but had an increase in N- and 6-O-sulfated domains demonstrating functional impairment of the HS2ST1. As heparan sulfate modulates FGF-mediated signaling, we found a significantly decreased activation of the MAP kinases ERK1/2 in FGF-2-stimulated cell lines of affected individuals that could be restored by addition of heparin, a GAG similar to heparan sulfate. Focal adhesions in FGF-2-stimulated fibroblasts of affected individuals concentrated at the cell periphery. Our data demonstrate that a heparan sulfate synthesis deficit causes a recognizable syndrome and emphasize a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal, and renal development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820632PMC
December 2020

Single-channel properties of skeletal muscle ryanodine receptor pore ΔFF in two brothers with a lethal form of fetal akinesia.

Cell Calcium 2020 05 17;87:102182. Epub 2020 Feb 17.

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, United States. Electronic address:

Ryanodine receptor ion channels (RyR1s) release Ca ions from the sarcoplasmic reticulum to regulate skeletal muscle contraction. By whole-exome sequencing, we identified the heterozygous RYR1 variant c.14767_14772del resulting in the in-frame deletion p.(Phe4923_Phe4924del) in two brothers with a lethal form of the fetal akinesia deformation syndrome (FADS). The two deleted phenylalanines (RyR1-ΔFF) are located in the S6 pore-lining helix of RyR1. Clinical features in one of the two siblings included severe hypotonia, thin ribs, swallowing inability, and respiratory insufficiency that caused early death. Functional consequences of the RyR1-ΔFF variant were determined using recombinant 2,200-kDa homotetrameric and heterotetrameric RyR1 channel complexes that were expressed in HEK293 cells and characterized by cellular, electrophysiological, and computational methods. Cellular Ca release in response to caffeine indicated that the homotetrameric variant formed caffeine-sensitive Ca conducting channels in HEK293 cells. In contrast, the homotetrameric channel complex was not activated by Ca and did not conduct Ca based on single-channel measurements. The computational analysis suggested decreased protein stability and loss of salt bridge interactions between RyR1-R4944 and RyR1-D4938, increasing the electrostatic interaction energy of Ca in a region 20 Å from the mutant site. Co-expression of wild-type and mutant RyR1s resulted in Ca-dependent channel activities that displayed intermediate Ca conductances and suggested maintenance of a reduced Ca release in the two patients. Our findings reveal that the RYR1 pore variant p.(Phe4923_Phe4924del) attenuates the flow of Ca through heterotetrameric channels, but alone was not sufficient to cause FADS, indicating additional genetic factors to be involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ceca.2020.102182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216825PMC
May 2020

Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.

Am J Med Genet A 2019 10 13;179(10):2056-2066. Epub 2019 Aug 13.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936249PMC
October 2019

Acute Liver Failure Meets SOPH Syndrome: A Case Report on an Intermediate Phenotype.

Pediatrics 2017 01;139(1)

Institute of Human Genetics and

Acute liver failure (ALF) is a life-threatening condition in the absence of preexisting liver disease in children. The main clinical presentation comprises hepatic dysfunction, elevated liver biochemical values, and coagulopathy. The etiology of ALF remains unclear in most affected children; however, the recent identification of mutations in the neuroblastoma amplified sequence (NBAS) gene in autosomal recessively inherited ALF has shed light on the cause of a subgroup of fever-triggered pediatric ALF episodes. Previously, biallelic mutations in NBAS have been reported to be associated with a syndrome comprising short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) specifically occurring in the Yakut population. No hepatic phenotype has been observed in individuals with this disorder who all carry the homozygous NBAS founder mutation c.5741G>A [p.(Arg1914His)]. We present the case of a 4-year-old girl with the cardinal features of SOPH syndrome: characteristic facial dysmorphism, postnatal growth retardation, delay of bone age, slender long bones, optic atrophy, and Pelger-Huët anomaly. During the first 2 years of her life, a series of infections with episodes of fever were accompanied by elevated liver enzyme levels, but hyperammonemia, hypoglycemia, coagulopathy, or encephalopathy suggestive of acute and severe liver disease were never observed. Whole exome sequencing in the patient revealed compound heterozygosity of the 2 NBAS variants, p.(Arg1914His) and p.(Glu943*). This case highlights the variability of clinical presentation associated with NBAS deficiency. Absence of severe liver problems in this case and SOPH-affected Yakut subjects suggests that individuals carrying the NBAS missense mutation p.(Arg1914His) are less susceptible to developing ALF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2016-0550DOI Listing
January 2017

Next-generation sequencing in X-linked intellectual disability.

Eur J Hum Genet 2015 Nov 4;23(11):1513-8. Epub 2015 Feb 4.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5-10% for X-chromosomal defects in male ID patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2015.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613482PMC
November 2015

Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome.

BMC Med Genet 2014 Nov 30;15:127. Epub 2014 Nov 30.

Institut für Medizinische Genetik und Humangenetik, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS.

Methods: Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment.

Results: Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP.

Conclusions: Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12881-014-0127-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412025PMC
November 2014

Deletions in the 3' part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome.

Hum Mutat 2014 Sep 8;35(9):1092-100. Epub 2014 Jul 8.

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22603DOI Listing
September 2014

Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities - support for the role of K(ATP) channels in this condition.

Eur J Med Genet 2013 Dec 28;56(12):678-82. Epub 2013 Oct 28.

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

KCNJ8 (NM_004982) encodes the pore forming subunit of one of the ATP-sensitive inwardly rectifying potassium (KATP) channels. KCNJ8 sequence variations are traditionally associated with J-wave syndromes, involving ventricular fibrillation and sudden cardiac death. Recently, the KATP gene ABCC9 (SUR2, NM_020297) has been associated with the multi-organ disorder Cantú syndrome or hypertrichotic osteochondrodysplasia (MIM 239850) (hypertrichosis, macrosomia, osteochondrodysplasia, and cardiomegaly). Here, we report on a patient with a de novo nonsynonymous KCNJ8 SNV (p.V65M) and Cantú syndrome, who tested negative for mutations in ABCC9. The genotype and multi-organ abnormalities of this patient are reviewed. A careful screening of the KATP genes should be performed in all individuals diagnosed with Cantú syndrome and no mutation in ABCC9.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2013.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902017PMC
December 2013

Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry.

Science 2013 Apr 21;340(6131):479-83. Epub 2013 Mar 21.

Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, Netherlands.

Glycosylated α-dystroglycan (α-DG) serves as cellular entry receptor for multiple pathogens, and defects in its glycosylation cause hereditary Walker-Warburg syndrome (WWS). At least eight proteins are critical to glycosylate α-DG, but many genes mutated in WWS remain unknown. To identify modifiers of α-DG, we performed a haploid screen for Lassa virus entry, a hemorrhagic fever virus causing thousands of deaths annually that hijacks glycosylated α-DG to enter cells. In complementary screens, we profiled cells for absence of α-DG carbohydrate chains or biochemically related glycans. This revealed virus host factors and a suite of glycosylation units, including all known Walker-Warburg genes and five additional factors critical for the modification of α-DG. Our findings accentuate the complexity of this posttranslational feature and point out genes defective in dystroglycanopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1233675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919138PMC
April 2013

Hyperphosphatasia-mental retardation syndrome due to PIGV mutations: expanded clinical spectrum.

Am J Med Genet A 2011 Aug 7;155A(8):1917-22. Epub 2011 Jul 7.

Institut für Medizinische Genetik und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Hyperphosphatasia-mental retardation syndrome is a recently delineated disorder associated with a recognizable facial phenotype and brachytelephalangy. This autosomal recessive condition is caused by homozygous and compound heterozygous missense mutations of PIGV, encoding a member of the GPI-anchor biosynthesis pathway. Here, we report on two further, unrelated patients with developmental delay, elevated serum levels of AP, distinctive facial features, hypoplastic terminal phalanges, anal atresia in one and Hirschsprung disease in the other patient. By sequencing PIGV we detected compound heterozygous mutations c.467G>A and c.1022C>A in Patient 1 and a homozygous mutation c.1022C>A in Patient 2. We reviewed the eight reported cases with proven PIGV mutations and re-defined the phenotypic spectrum associated with PIGV mutations: intellectual disability, the distinct facial gestalt, brachytelephalangy, and hyperphosphatasia are constant features but also anorectal malformations and Hirschsprung disease as well as cleft lip/palate and hearing impairment should be considered as part of the clinical spectrum. Moreover, seizures and muscular hypotonia are frequently associated with PIGV mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.34102DOI Listing
August 2011

Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity.

Nat Genet 2011 Feb 9;43(2):132-7. Epub 2011 Jan 9.

Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg, Freiburg, Germany.

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.749DOI Listing
February 2011

Wiedemann-Steiner syndrome: three further cases.

Am J Med Genet A 2010 Sep;152A(9):2372-5

Institut für Humangenetik der Johann Wolfgang Goethe Universität, Frankfurt, Germany.

We describe three patients with a syndrome comprising arched, thick eyebrows, hypertelorism, narrow palpebral fissures, broad nasal bridge and tip, long philtrum, thin upper lip, stubby hands and feet, hirsutism, and severe psychomotor retardation. These patients expand the phenotype of the Wiedemann-Steiner syndrome and delineate it as an entity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.33587DOI Listing
September 2010

Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome.

Nat Genet 2010 Oct 29;42(10):827-9. Epub 2010 Aug 29.

Max Planck Institute for Molecular Genetics, Berlin, Germany.

Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.653DOI Listing
October 2010

A de novo unbalanced translocation leading to partial monosomy 9p23-pter and partial trisomy 15q25.3-qter associated with 46,XY complete gonadal dysgenesis, tall stature and mental retardation.

Clin Dysmorphol 2010 Oct;19(4):190-4

Institut für Humangenetik, Lübeck, Germany.

Syndromic forms of disorders of sex development constitute a challenge for clinical and molecular investigations. We report on a 12-year-old girl presenting with lack of pubertal development, tall stature and moderate mental retardation. Conventional karyotyping at the age of 3 years revealed a male karyotype (46,XY). At the age of 12 years, the girl had no signs of puberty, and laboratory values were consistent with hypergonadotropic hypogonadism because of complete gonadal dysgenesis. Histology at the time of gonadectomy revealed fibrous tissue without testicular morphology. Cytogenetic reevaluation at that time showed additional material of unknown origin on the short arm of chromosome 9. Subsequent fluorescence in-situ hybridization and Array-CGH analyses revealed an unbalanced translocation between 9p and 15q resulting in a partial monosomy of 9p and a partial trisomy of 15q. The karyotype was described as 46,XY,der(9)t(9;15)(p23;q25.3). We discuss the clinical and molecular cytogenetic findings with respect to the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCD.0b013e32833c8ba1DOI Listing
October 2010

Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: Five new patients with Mabry syndrome.

Am J Med Genet A 2010 Jul;152A(7):1661-9

Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Persistent hyperphosphatasia associated with developmental delay and seizures was described in a single family by Mabry et al. 1970 (OMIM 239300), but the nosology of this condition has remained uncertain ever since. We report on five new patients (two siblings, one offspring of consanguineous parents, and two sporadic patients) that help delineate this distinctive disorder and provide evidence in favor of autosomal recessive inheritance. Common to all five new patients is facial dysmorphism, namely hypertelorism, a broad nasal bridge and a tented mouth. All patients have some degree of brachytelephalangy but the phalangeal shortening varies in position and degree. In all, there is a persistent elevation of alkaline phosphatase activity without any evidence for active bone or liver disease. The degree of hyperphosphatasia varies considerably ( approximately 1.3-20 times the upper age-adjusted reference limit) between patients, but is relatively constant over time. In the first family described by Mabry et al. 1970, at least one member was found to have intracellular inclusions on biopsy of some but not all tissues. This was confirmed in three of our patients, but the inclusions are not always observed and the intracellular storage material has not been identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.33438DOI Listing
July 2010

A variant of Desbuquois dysplasia characterized by advanced carpal bone age, short metacarpals, and elongated phalanges: report of seven cases.

Am J Med Genet A 2010 Apr;152A(4):875-85

Department of Radiology, Ajou University Hospital, Suwon, South Korea.

We present the clinical and radiological findings of seven patients with a seemingly new variant of Desbuquois dysplasia (DBQD) and emphasize the radiographic findings in the hand. All cases showed remarkably accelerated carpal bone ages in childhood, but none of the patients had an accessory ossification center distal to the second metacarpal, or thumb anomalies, instead, there was shortness of one or all metacarpals, with elongated appearance of phalanges, resulting in nearly equal length of the second to fifth fingers. The two sibs followed for 20 years showed narrowing and fusion of the intercarpal joints with age and ultimately, precocious degenerative arthritis. The changes in the feet were similar to those of the hands, with advanced tarsal bone ages, shortness of the metatarsals and elongation of the second and third toes. Other radiographic findings were narrowness of the intervertebral disc spaces resulting in precocious degenerative spondylosis and progressive scoliosis. The femoral neck was short and thick and showed a persistent enlargement of the lesser trochanter with a high-riding, bulbous greater trochanter that became more prominent with age. Molecular testing of the diastrophic dysplasia sulfate transporter (DTDST) gene was performed on six patients and no mutations were detected. This radiographic and clinical observation further adds to the evidence that there may be subtypes of DBQD. Long-term follow-up showed that severe precocious osteoarthritis of the hand and spine is a major manifestation of this specific variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.33347DOI Listing
April 2010

Mosaic and complete tetraploidy in live-born infants: two new patients and review of the literature.

Clin Dysmorphol 2010 Jul;19(3):123-7

Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.

Tetraploidy is a very rare finding in live-born infants. Nine infants with tetraploidy have been reported earlier. The phenotype is of variable severity and consists of prenatal and/or postnatal growth retardation, developmental delay, mental retardation, dysmorphic features, and skeletal and internal abnormalities. Here we present a girl aged 2 years and 7 months with a mosaic tetraploidy detected in lymphocytes, and a newborn boy with a complete tetraploidy, who died 30 h after birth. They both show growth retardation, microcephaly, developmental delay, and craniofacial dysmorphisms. The clinical features of 22 patients reported earlier are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCD.0b013e3283353877DOI Listing
July 2010

Hyperphosphatasia with mental retardation, brachytelephalangy, and a distinct facial gestalt: Delineation of a recognizable syndrome.

Eur J Med Genet 2010 Mar-Apr;53(2):85-8. Epub 2010 Jan 18.

Institut für Medizinische Genetik, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

The association of mental retardation and persistent hyperphosphatasia has been described in rare instances. Because of parental consanguinity and sib recurrences autosomal recessive inheritance has been proposed. We report three sibs with a syndrome consisting of severe mental retardation, considerably elevated serum levels of alkaline phosphatase, hypoplastic terminal phalanges, and distinct facial features. Clinically and radiologically, shortness of distal phalanges could be demonstrated in all of them. Their particular facial appearance led us to two earlier reported familial cases with convincing clinical similarities. We suggest a specific clinical entity within the spectrum of patients with mental retardation and hyperphosphatasia, which is in particular characterized by a recognizable facial gestalt and brachytelephalangy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2010.01.002DOI Listing
July 2010

Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.

Am J Hum Genet 2009 Apr 26;84(4):483-92. Epub 2009 Mar 26.

Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.

Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed. A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. The duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2009.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667973PMC
April 2009

Goltz-Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap.

Eur J Hum Genet 2009 Oct 11;17(10):1207-15. Epub 2009 Mar 11.

Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2009.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986635PMC
October 2009

Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father.

Am J Med Genet A 2008 Mar;146A(6):779-83

Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.

We report on a 5-year-old boy with spondylocarpotarsal synostosis (SCT) syndrome who presents with disproportionate short stature, thoracic scoliosis, pes planus, dental enamel hypoplasia, unilateral conductive hearing loss and mild facial dysmorphisms. Radiographs showed abnormal segmentation of the spine with block vertebrae and carpal synostosis. In addition to the typical phenotype of SCT syndrome, he showed pronounced delay of carpal bone age and bilateral epiphyseal dysplasia of the proximal femora. The patient's father has mild short stature and unilateral hip dysplasia. Molecular studies of the filamin B gene (FLNB) revealed a homozygous mutation in the index patient while both parents were heterozygous for the mutation. In this report we expand the phenotype of SCT syndrome in a patient with a causal FLNB mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.32230DOI Listing
March 2008

Mutations in the pericentrin (PCNT) gene cause primordial dwarfism.

Science 2008 Feb 3;319(5864):816-9. Epub 2008 Jan 3.

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1151174DOI Listing
February 2008

SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.

J Med Genet 2007 Oct 23;44(10):651-6. Epub 2007 Jun 23.

Background: Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS.

Methods And Results: We investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene.

Conclusion: We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmg.2007.051276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597961PMC
October 2007

Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation.

Am J Hum Genet 2007 Mar 29;80(3):550-60. Epub 2007 Jan 29.

Institute of Human Genetics, Friedrich Alexander University Erlangen Nuremberg, Erlangen, Germany.

We observed two unrelated consanguineous families with malformation syndromes sharing anophthalmia and distinct eyebrows as common signs, but differing for alveolar capillary dysplasia or complex congenital heart defect in one and diaphragmatic hernia in the other family. Homozygosity mapping revealed linkage to a common locus on chromosome 15, and pathogenic homozygous mutations were identified in STRA6, a member of a large group of "stimulated by retinoic acid" genes encoding novel transmembrane proteins, transcription factors, and secreted signaling molecules or proteins of largely unknown function. Subsequently, homozygous STRA6 mutations were also demonstrated in 3 of 13 patients chosen on the basis of significant phenotypic overlap to the original cases. While a homozygous deletion generating a premature stop codon (p.G50AfsX22) led to absence of the immunoreactive protein in patient's fibroblast culture, structural analysis of three missense mutations (P90L, P293L, and T321P) suggested significant effects on the geometry of the loops connecting the transmembrane helices of STRA6. Two further variations in the C-terminus (T644M and R655C) alter specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the "STRA" group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/512203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1821097PMC
March 2007

A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.

Nature 2006 Dec;444(7122):1038-43

Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature05456DOI Listing
December 2006

Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.

J Med Genet 2007 Feb 20;44(2):131-5. Epub 2006 Oct 20.

Institute of Human Genetics, University of Erlangen-Nuremberg, Germany.

Background: Noonan syndrome, cardio-facio-cutaneous syndrome (CFC) and Costello syndrome constitute a group of developmental disorders with an overlapping pattern of congenital anomalies. Each of these conditions can be caused by germline mutations in key components of the highly conserved Ras-MAPK pathway, possibly reflecting a similar pathogenesis underlying the three disorders. Germline mutations in KRAS have recently been identified in a small number of patients with Noonan syndrome and CFC.

Methods And Results: 260 patients were screened for KRAS mutations by direct sequencing. Overall, we detected KRAS mutations in 12 patients, including three known and eight novel sequence alterations. All mutations are predicted to cause single amino acid substitutions. Remarkably, our cohort of individuals with KRAS mutations showed a high clinical variability, ranging from Noonan syndrome to CFC, and also included two patients who met the clinical criteria of Costello syndrome.

Conclusion: Our findings reinforce the picture of a clustered distribution of disease associated KRAS germline alterations. We further defined the phenotypic spectrum associated with KRAS missense mutations and provided the first evidence of clinical differences in patients with KRAS mutations compared with Noonan syndrome affected individuals with heterozygous PTPN11 mutations and CFC patients carrying a BRAF, MEK1 or MEK1 alteration, respectively. We speculate that the observed phenotypic variability may be related, at least in part, to specific genotypes and possibly reflects the central role of K-Ras in a number of different signalling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmg.2006.046300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2598066PMC
February 2007

Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.

Am J Hum Genet 2006 Nov 6;79(5):878-89. Epub 2006 Sep 6.

Institut fur Humangenetik, Universitatsklinikum Hamburg-Eppendorf, Butenfeld 42, Hamburg, Germany.

The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations--a missense mutation (p.R217C) and a nonsense mutation (p.R197X)--in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c-type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c(1). We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal-truncated Delta 197-268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c-type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c-mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/508474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698567PMC
November 2006

Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification.

Eur J Med Genet 2005 Oct-Dec;48(4):397-411. Epub 2005 Jun 8.

Institut für Humangenetik, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany.

Oculo-auriculo-vertebral spectrum (OMIM164210) is a phenotypically and probably also a genetically heterogeneous disorder, characterized by anomalies of the ear (mostly microtia), hemifacial microsomia, and defects of the vertebral column. Associated clinical findings include anomalies of the eye and brain, and developmental delay. We have evaluated the clinical data and photographs of 53 unrelated patients with OAVS, all presenting with either isolated microtia or preauricular tags in association with hemifacial microsomia as minimal diagnostic criteria; five had a positive family history for OAVS. Based on the main clinical findings and unilateral or bilateral involvement, we have developed a new classification system for OAVS, consisting of six subgroups. There is a statistically significant correlation between the subgroup and number of associated clinical findings, and a statistically significant difference regarding prognosis in uni- and bilaterally affected patients, suggesting that this classification is clinically relevant to the categorization of patients with OAVS. The newly developed scoring system (two points for each main clinical finding and one for each associated clinical finding) presented here, also aids prognosis, especially for delay of motor development and brain anomalies, and statistical analysis revealed significant clustering between different clinical findings of OAVS confirming the clinical impression previously published by several authors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2005.04.015DOI Listing
February 2006

Clinical and mutational spectrum of Mowat-Wilson syndrome.

Eur J Med Genet 2005 Apr-Jun;48(2):97-111. Epub 2005 Feb 25.

Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2005.01.003DOI Listing
September 2005

An unusual combination of EEC syndrome and hypomelanosis Ito due to a p63 mutation.

Eur J Pediatr 2005 Aug 12;164(8):530-1. Epub 2005 May 12.

Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-005-1680-5DOI Listing
August 2005