Publications by authors named "Irina Hüning"

13 Publications

  • Page 1 of 1

Heterogeneous phenotypes in families with duplications of the paternal allele within the imprinting center 1 (H19/IGF2:TSS-DMR) in 11p15.5.

Clin Genet 2020 10 9;98(4):418-419. Epub 2020 Aug 9.

Institute of Human Genetics, University of Würzburg, Würzburg, Germany.

The clinical impact of duplications affecting the 11p15.5 region is difficult to predict, and depends on the parent-of-origin of the affected allele as well as on the type (deletion, duplication), the extent and genomic content of the variant. Three unrelated families with inheritance of duplications affecting the IC1 region in 11p15.5 through two generations but different phenotypes (Beckwith-Wiedemann and Silver-Russell syndromes, normal phenotype) are reported. The inconsistent phenotypic patterns of carriers of the same variant strongly indicate the impact of cis- and/or trans-acting modifiers on the clinical outcome of IC1 duplication carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13820DOI Listing
October 2020

Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia.

Parkinsonism Relat Disord 2020 08 29;77:70-75. Epub 2020 Jun 29.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany; Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.

Introduction: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation.

Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed.

Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date.

Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2020.06.027DOI Listing
August 2020

Identification of the recently described plasminogen gene mutation p.Lys330Glu in a family from Northern Germany with hereditary angioedema.

Clin Transl Allergy 2019 14;9. Epub 2019 Feb 14.

1Department of Dermatology, Allergology and Venereology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.

Hereditary angioedema (HAE) is a life-threatening disease characterized by recurrent episodes of subcutaneous and mucosal swellings and abdominal cramping. Corticosteroids and antihistamines, which are usually beneficial in histamine-induced acquired angioedema, are not effective in HAE. Therefore, diagnosing HAE correctly is crucial for affected patients. We report a family from Northern Germany with six individuals suffering from recurrent swellings, indicating HAE. Laboratory tests and genetic diagnostics of the genes , encoding C1 esterase inhibitor (C1-INH), and encoding coagulation factor XII, were unremarkable. In three affected and one yet unaffected member of the family, we were then able to identify the c.988A > G (also termed c.1100A > G) mutation in the ( gene, which has recently been described in several families with HAE. This mutation leads to a missense mutation with an amino acid exchange p.Lys330Glu in the kringle 3 domain of plasminogen. There was no direct relationship between the earlier described cases with this mutation and the family we report here. In all affected members of the family, the symptoms manifested in adulthood, with swellings of the face, tongue and larynx, including a fatal case of a 19 year-old female individual. The frequency of the attacks was variable, ranging between once per year to once a month. In one individual, we also found decreased serum levels of plasminogen as well as coagulation factor XII. As previously reported in patients with PLG defects, icatibant proved to be very effective in controlling acute attacks, indicating an involvement of bradykinin in the pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13601-019-0247-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374890PMC
February 2019

A KAT6A variant in a family with autosomal dominantly inherited microcephaly and developmental delay.

J Hum Genet 2018 Sep 13;63(9):997-1001. Epub 2018 Jun 13.

Institute of Neurogenetics, University of Lübeck, 23538, Lübeck, Germany.

Approximately 1-3% of children have intellectual disability or global developmental delay. Heterozygous mutations have emerged as a major cause of different intellectual disability syndromes. In severely affected patients, reproductive fitness is impaired and mutations have usually arisen de novo. Massive parallel sequencing has been an effective means of diagnosing patients, especially those who carry a de novo mutation. The molecular diagnosis can be a way to shift from a more phenotype-driven management of the clinical signs to a more refined treatment based on genotype. Here, we report a novel dominantly inherited KAT6A missense variant in the C-terminal transactivation domain identified by exome sequencing in a girl and her father. Both had intellectual disability/developmental delay, short stature, microcephaly, and strabismus with the father being mildly affected. We here report the first inherited variant in KAT6A and suggest missense variants in KAT6A to be associated with an inheritable, milder clinical presentation compared to previously reported de novo, truncating mutations in this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-018-0469-0DOI Listing
September 2018

A novel de novo mutation in CSNK2A1: reinforcing the link to neurodevelopmental abnormalities and dysmorphic features.

J Hum Genet 2017 Nov 20;62(11):1005-1006. Epub 2017 Jul 20.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jhg.2017.73DOI Listing
November 2017

Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.

Hum Mol Genet 2017 03;26(6):1078-1086

Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.

Global developmental delay (GDD), often accompanied by intellectual disability, seizures and other features is a severe, clinically and genetically highly heterogeneous childhood-onset disorder. In cases where genetic causes have been identified, de novo mutations in neuronally expressed genes are a common scenario. These mutations can be best identified by exome sequencing of parent-offspring trios. De novo mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) gene, encoding the Gβ1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD. Using exome sequencing, we identified 14 different novel variants (2 splice site, 2 frameshift and 10 missense changes) in GNB1 in 16 pediatric patients. One mutation (R96L) was recurrently found in three ethnically diverse families with an autosomal dominant mode of inheritance. Ten variants occurred de novo in the patients. Missense changes were functionally tested for their pathogenicity by assaying the impact on complex formation with Gγ and resultant mutant Gβγ with Gα. Signaling properties of G protein complexes carrying mutant Gβ1 subunits were further analyzed by their ability to couple to dopamine D1R receptors by real-time bioluminescence resonance energy transfer (BRET) assays. These studies revealed altered functionality of the missense mutations R52G, G64V, A92T, P94S, P96L, A106T and D118G but not for L30F, H91R and K337Q. In conclusion, we demonstrate a pathogenic role of de novo and autosomal dominant mutations in GNB1 as a cause of GDD and provide insights how perturbation in heterotrimeric G protein function contributes to the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddx018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075543PMC
March 2017

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

Neurology 2016 07 8;87(1):77-85. Epub 2016 Jun 8.

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24.

Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24).

Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function.

Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000002807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932231PMC
July 2016

Fibrodysplasia ossificans progressiva: clinical course, genetic mutations and genotype-phenotype correlation.

Mol Syndromol 2014 Aug 7;5(5):201-11. Epub 2014 Aug 7.

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

Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare autosomal dominant genetic disorder and the most disabling condition of heterotopic (extraskeletal) ossification in humans. Mutations in the ACVR1 gene (MIM 102576) were identified as a genetic cause of FOP [Shore et al., 2006]. Most patients with FOP have the same recurrent single nucleotide change c.617G>A, p.R206H in the ACVR1 gene. Furthermore, 11 other mutations in the ACVR1 gene have been described as a cause of FOP. Here, we review phenotypic and molecular findings of 130 cases of FOP reported in the literature from 1982 to April 2014 and discuss possible genotype-phenotype correlations in FOP patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000365770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188166PMC
August 2014

Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures.

Am J Med Genet A 2014 Aug 5;164A(8):1976-80. Epub 2014 May 5.

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

In patients with genetically heterogeneous disorders such as intellectual disability or epilepsy, exome sequencing is a powerful tool to elucidate the underlying genetic cause. Homozygous and compound heterozygous mutations in C12orf57 have recently been described to cause an autosomal recessive syndromic form of intellectual disability, including agenesis/hypoplasia of the corpus callosum, optic coloboma, and intractable seizures. Here, we report on two siblings from nonconsanguineous parents harboring two compound heterozygous loss-of-function mutations in C12orf57 identified by exome sequencing, including a novel nonsense mutation, and review the patients described in the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36592DOI Listing
August 2014

High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors.

Mol Genet Genomic Med 2014 Mar 14;2(2):176-85. Epub 2014 Jan 14.

Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald Greifswald, Germany.

Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960060PMC
March 2014

Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.

Epilepsia 2014 Apr 1;55(4):e25-9. Epub 2014 Mar 1.

Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.

Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the αII -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.12554DOI Listing
April 2014

Exon 2 duplication of the MID1 gene in a patient with a mild phenotype of Opitz G/BBB syndrome.

Eur J Med Genet 2013 Apr 23;56(4):188-91. Epub 2013 Jan 23.

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

The X-linked form of Opitz G/BBB syndrome is a congenital midline malformation syndrome caused by MID1 loss-of-function mutations, including point mutations and small-sized duplications, insertions, and deletions. Three patients with an Opitz G/BBB syndrome phenotype and relatively large duplications of part of the MID1 gene have been described up to date. Here we report a 2-months-old boy with a very mild phenotype including craniofacial dysmorphism, swallowing difficulties, and a normal psychomotor development. Molecular karyotyping revealed a 57-kb duplication involving exon 2 of the MID1 gene. The in-frame tandem duplication was confirmed by MID1 transcript analysis. This alteration results likely in a mutant MID1 protein which contains 32 duplicated amino acids in the first part of the coiled-coil domain. The mild phenotype of the patient with the microduplication suggests that MID1 mutations can be found in patients with hypertelorism with or without other clinical signs and MID1 alterations might be missed in individuals not fulfilling the minimal criteria for diagnosis of X-linked Opitz G/BBB syndrome. This report further emphasizes the genotype-first approach in medical genetics in general and patients with unspecific clinical features in particular.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2013.01.004DOI Listing
April 2013

Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization.

Am J Hum Genet 2012 Nov 11;91(5):897-905. Epub 2012 Oct 11.

Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2012.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487118PMC
November 2012