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Article ; Online: Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes.

Luukkonen, Tiia Maria / Mehrjouy, Mana M / Pöyhönen, Minna / Anttonen, Anna-Kaisa / Lahermo, Päivi / Ellonen, Pekka / Paulin, Lars / Tommerup, Niels / Palotie, Aarno / Varilo, Teppo

Molecular genetics & genomic medicine

2017 Volume 6, Issue 1, Page(s) 56–68

Abstract: ... estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43 ... This study demonstrates a balanced t(1;12)(q43;q21.1) with conserved haplotypes on the derived chromosomes ...

Abstract	Background: The risk of serious congenital anomaly for de novo balanced translocations is estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a "Systematic Survey of Balanced Chromosomal Rearrangements in Finns." In the first family, carriers (n = 6) manifest with learning problems in childhood, and later with unexplained neurological symptoms (chronic headache, balance problems, tremor, fatigue) and cerebral infarctions in their 50s. In the second family, two carriers suffer from tetralogy of Fallot, one from transient ischemic attack and one from migraine. The translocation cosegregates with these vascular phenotypes and neurological symptoms. Methods and results: We narrowed down the breakpoint regions using mate pair sequencing. We observed conserved haplotypes around the breakpoints, pointing out that this translocation has arisen only once. The chromosome 1 breakpoint truncates a CHRM3 processed transcript, and is flanked by the 5' end of CHRM3 and the 3' end of RYR2. TRHDE, KCNC2, and ATXN7L3B flank the chromosome 12 breakpoint. Conclusions: This study demonstrates a balanced t(1;12)(q43;q21.1) with conserved haplotypes on the derived chromosomes. The translocation seems to result in vascular phenotype, with or without neurological symptoms, in at least two families. We suggest that the translocation influences the positional expression of CHRM3, RYR2, TRHDE, KCNC2, and/or ATXN7L3B.
MeSH term(s)	Adult ; Aged ; Base Sequence ; Chromosome Aberrations ; Chromosome Breakpoints ; Chromosome Mapping/methods ; Chromosomes, Human, Pair 1/genetics ; Chromosomes, Human, Pair 12/genetics ; Female ; Finland ; Haplotypes/genetics ; Heterozygote ; Humans ; Karyotyping/methods ; Male ; Middle Aged ; Pedigree ; Phenotype ; Receptor, Muscarinic M3/genetics ; Ryanodine Receptor Calcium Release Channel/genetics ; Shaw Potassium Channels/genetics ; Transcription Factors/genetics ; Translocation, Genetic/genetics
Chemical Substances	ATXN7L3B protein, human ; CHRM3 protein, human ; KCNC2 protein, human ; Receptor, Muscarinic M3 ; RyR2 protein, human ; Ryanodine Receptor Calcium Release Channel ; Shaw Potassium Channels ; Transcription Factors
Language	English
Publishing date	2017-11-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2734884-2
ISSN	2324-9269 ; 2324-9269
ISSN (online)	2324-9269
ISSN	2324-9269
DOI	10.1002/mgg3.346
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Article ; Online: The Finnish genetic heritage in 2022 - from diagnosis to translational research.

Uusimaa, Johanna / Kettunen, Johannes / Varilo, Teppo / Järvelä, Irma / Kallijärvi, Jukka / Kääriäinen, Helena / Laine, Minna / Lapatto, Risto / Myllynen, Päivi / Niinikoski, Harri / Rahikkala, Elisa / Suomalainen, Anu / Tikkanen, Ritva / Tyynismaa, Henna / Vieira, Päivi / Zarybnicky, Tomas / Sipilä, Petra / Kuure, Satu / Hinttala, Reetta

Disease models & mechanisms

2022 Volume 15, Issue 10

Abstract: Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal- ...

Abstract	Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype-phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.
MeSH term(s)	Finland/epidemiology ; Translational Research, Biomedical ; Phenotype
Language	English
Publishing date	2022-10-26
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.049490
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Article ; Online: The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia.

Hakkarainen, Marja / Kaaja, Ilse / Douglas, Suvi P M / Vulliamy, Tom / Dokal, Inderjeet / Soulier, Jean / Larcher, Lise / Peffault de Latour, Régis / Leblanc, Thierry / Sicre de Fontbrune, Flore / Siitonen, Timo / Lohi, Olli / Hellström-Lindberg, Eva / Barbany, Gisela / Tesi, Bianca / Shimamura, Akiko / Beier, Fabian / Jackson, Sharon / Kuperman, Amir Asher /

Falik Zaccai, Tzipora / Tamary, Hannah / Mecucci, Cristina / Capolsini, Ilaria / Jahnukainen, Kirsi / Salmenniemi, Urpu / Niinimäki, Riitta / Varilo, Teppo / Kilpivaara, Outi / Wartiovaara-Kautto, Ulla

Blood

2023 Volume 141, Issue 23, Page(s) 2853–2866

Abstract: Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of ...

Abstract	Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). The subjects presented with 19 different variants of ERCC6L2, and we identified a founder mutation, c.1424delT, in Finnish patients. The median age of the subjects at baseline was 18 years (range, 2-65 years). Changes in the complete blood count were mild despite severe bone marrow (BM) hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without HMs. Signs of progressive disease included increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in the BM morphology. The median age at the onset of HM was 37.0 years (95% CI, 31.5-42.5; range, 12-65 years). The overall survival (OS) at 3 years was 95% (95% CI, 85-100) and 19% (95% CI, 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome with a 3-year OS of 28% (95% CI, 0-61). Our results demonstrated the importance of early recognition and active surveillance in patients with biallelic germ line ERCC6L2 variants.
MeSH term(s)	Humans ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Retrospective Studies ; Bone Marrow Failure Disorders ; Leukemia, Myeloid, Acute/genetics ; Anemia, Aplastic/genetics ; DNA Repair ; Pancytopenia ; Acute Disease ; DNA Helicases/genetics
Chemical Substances	ERCC6L2 protein, human (EC 3.6.4.12) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2023-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022019425
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Article: Isolates and their potential use in complex gene mapping efforts.

Varilo, Teppo / Peltonen, Leena

Current opinion in genetics & development

2004 Volume 14, Issue 3, Page(s) 316–323

Abstract: Linkage disequilibrium (LD), detectable with microsatellites in disease alleles over wide genetic intervals in population isolates, has facilitated mapping and positional cloning of numerous disease genes. We, among others, have shown that the LD ... ...

Abstract	Linkage disequilibrium (LD), detectable with microsatellites in disease alleles over wide genetic intervals in population isolates, has facilitated mapping and positional cloning of numerous disease genes. We, among others, have shown that the LD intervals reach up to 1 Mb in general alleles of young subisolates, and that this feature most probably offers an avenue for the initial locus positioning for complex traits. Development of efficient SNP genotyping and characterization of haploblock structure of the human genome have introduced new prospects to LD-based fine mapping and haplotype-association studies. Encouraging associations have been reported for several complex diseases. Final breakthroughs in mapping of complex disease loci have emerged on large pedigrees in population isolates. Conversely, ignoring genealogical makeup of the study population seems to disclose false negative and false positive associations, directing resources down the drain.
MeSH term(s)	Chromosome Mapping ; Genetic Diseases, Inborn/genetics ; Genetic Predisposition to Disease/genetics ; Genetics, Population ; Humans ; Linkage Disequilibrium ; Pedigree ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2004-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2004.04.008
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Zs.A 3240: Show issues

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Article ; Online: A genome-wide screen for acrophobia susceptibility loci in a Finnish isolate.

Misiewicz, Zuzanna / Hiekkalinna, Tero / Paunio, Tiina / Varilo, Teppo / Terwilliger, Joseph D / Partonen, Timo / Hovatta, Iiris

Scientific reports

2016 Volume 6, Page(s) 39345

Abstract: Acrophobia, an abnormal fear of heights, is a specific phobia characterized as apprehension cued by the occurrence or anticipation of elevated spaces. It is considered a complex trait with onset influenced by both genetic and environmental factors. ... ...

Abstract	Acrophobia, an abnormal fear of heights, is a specific phobia characterized as apprehension cued by the occurrence or anticipation of elevated spaces. It is considered a complex trait with onset influenced by both genetic and environmental factors. Identification of genetic risk variants would provide novel insight into the genetic basis of the fear of heights phenotype and contribute to the molecular-level understanding of its aetiology. Genetic isolates may facilitate identification of susceptibility alleles due to reduced genetic heterogeneity. We took advantage of an internal genetic isolate in Finland in which a distinct acrophobia phenotype appears to be segregating in pedigrees originally ascertained for schizophrenia. We conducted parametric, nonparametric, joint linkage and linkage disequilibrium analyses using a microsatellite marker panel, genotyped in families to search for chromosomal regions correlated with acrophobia. Our results implicated a few regions with suggestive evidence for linkage on chromosomes 4q28 (LOD = 2.17), 8q24 (LOD = 2.09) and 13q21-q22 (LOD = 2.22). We observed no risk haplotypes shared between different families. These results suggest that genetic predisposition to acrophobia in this genetic isolate is unlikely to be mediated by a small number of shared high-risk alleles, but rather has a complex genetic architecture.
MeSH term(s)	Alleles ; Anticipation, Psychological/physiology ; Chromosome Mapping ; Female ; Finland ; Genetic Linkage/genetics ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Haplotypes/genetics ; Humans ; Male ; Microsatellite Repeats/genetics ; Pedigree ; Phobic Disorders/genetics ; Polymorphism, Single Nucleotide/genetics ; Schizophrenia/genetics
Language	English
Publishing date	2016--20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep39345
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Article: Haplotype analysis and identification of genes for a complex trait: examples from schizophrenia.

Hennah, William / Varilo, Teppo / Paunio, Tiina / Peltonen, Leena

Annals of medicine

2004 Volume 36, Issue 5, Page(s) 322–331

Abstract: For more than a decade there has been intensive research into the genetic etiology of schizophrenia, yet it is only recently that the first findings of promising genes associating with the disorder have been reported. Linkage analyses in families ... ...

Abstract	For more than a decade there has been intensive research into the genetic etiology of schizophrenia, yet it is only recently that the first findings of promising genes associating with the disorder have been reported. Linkage analyses in families collected from different populations have provided relatively well defined genomic loci. These have been typically followed by fine mapping studies using single nucleotide polymorphisms (SNPs). A number of analysis programs have been produced to test SNPs and their haplotypes for association. Typically association has been established to specific haplotypes representing an allelic variant of the corresponding gene. The inherent problem of multiple testing in the analysis of haplotypes needs to be addressed fully, to determine if any of these recent findings can be considered as confirmed susceptibility genes for schizophrenia. However, informative haplotypes have provided a way to define allelic variants of genes associated with schizophrenia in numerous study samples, and are a useful tool in characterizing the extent of allelic diversity of putative schizophrenia susceptibility genes within different populations.
MeSH term(s)	Chromosome Mapping/methods ; Chromosomes, Human, Pair 1/genetics ; Chromosomes, Human, Pair 13/genetics ; Chromosomes, Human, Pair 22/genetics ; Chromosomes, Human, Pair 6/genetics ; Chromosomes, Human, Pair 8/genetics ; Genetic Predisposition to Disease/genetics ; Genome, Human ; Haplotypes/genetics ; Humans ; Linkage Disequilibrium/genetics ; Polymorphism, Single Nucleotide ; Schizophrenia/genetics
Language	English
Publishing date	2004-09-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1004226-x
ISSN	1365-2060 ; 1651-2219 ; 0785-3890 ; 1743-1387
ISSN (online)	1365-2060 ; 1651-2219
ISSN	0785-3890 ; 1743-1387
DOI	10.1080/07853890410029824
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Article ; Online: Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.

Järvelä, Irma / Määttä, Tuomo / Acharya, Anushree / Leppälä, Juha / Jhangiani, Shalini N / Arvio, Maria / Siren, Auli / Kankuri-Tammilehto, Minna / Kokkonen, Hannaleena / Palomäki, Maarit / Varilo, Teppo / Fang, Mary / Hadley, Trevor D / Jolly, Angad / Linnankivi, Tarja / Paetau, Ritva / Saarela, Anni / Kälviäinen, Reetta / Olme, Jan /

Nouel-Saied, Liz M / Cornejo-Sanchez, Diana M / Llaci, Lorida / Lupski, James R / Posey, Jennifer E / Leal, Suzanne M / Schrauwen, Isabelle

Human genetics

2021 Volume 140, Issue 7, Page(s) 1011–1029

Abstract: The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used ... ...

Abstract	The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.
MeSH term(s)	Exome/genetics ; Family ; Female ; Finland ; Genes, Recessive/genetics ; Genetic Predisposition to Disease/genetics ; Genotype ; Homozygote ; Humans ; Intellectual Disability/genetics ; Male ; Pedigree ; Whole Exome Sequencing/methods
Language	English
Publishing date	2021-03-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-021-02268-1
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Article ; Online: Does originating from a genetic isolate affect the level of cognitive impairments in schizophrenia families?

Torniainen, Minna / Wedenoja, Juho / Varilo, Teppo / Partonen, Timo / Suokas, Jaana / Häkkinen, Laura / Lönnqvist, Jouko / Suvisaari, Jaana / Tuulio-Henriksson, Annamari

Psychiatry research

2013 Volume 208, Issue 2, Page(s) 111–117

Abstract: Earlier studies have detected differences in the prevalence, symptomatology and genetic risk variants of schizophrenia between a north-eastern Finnish genetic isolate and the rest of Finland. This study compared a population-based isolate sample (145 ... ...

Abstract	Earlier studies have detected differences in the prevalence, symptomatology and genetic risk variants of schizophrenia between a north-eastern Finnish genetic isolate and the rest of Finland. This study compared a population-based isolate sample (145 persons with schizophrenia, 304 first-degree relatives and 32 controls) with a rest of Finland sample (73 persons with schizophrenia, 100 first-degree relatives and 80 controls) in cognitive functioning. Persons from the isolate outperformed persons in the rest of Finland sample in verbal learning, verbal ability and cognitive flexibility in the schizophrenia groups and in verbal learning, speeded processing and attentional control in the relatives groups. The differences between the subsamples remained significant after taking into account an intragenic Reelin STR allele, previously associated with cognitive impairments and almost absent from the isolate, in addition to disorder characteristics and familial loading. In control groups, we observed no differences between the isolate and the rest of Finland. In conclusion, cognitive impairments were milder in schizophrenia patients and their first-degree relatives within than outside the isolate. An absence of differences between the control samples suggests that the differences in schizophrenia families may relate to genetic background, possibly to partly distinct variants affecting the liability inside and outside the isolate.
MeSH term(s)	Adult ; Aged ; Alleles ; Case-Control Studies ; Cell Adhesion Molecules, Neuronal/genetics ; Cognition Disorders/complications ; Cognition Disorders/genetics ; Cognition Disorders/psychology ; Extracellular Matrix Proteins/genetics ; Family/psychology ; Family Health ; Female ; Finland ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Middle Aged ; Nerve Tissue Proteins/genetics ; Neuropsychological Tests ; Schizophrenia/complications ; Schizophrenia/genetics ; Schizophrenic Psychology ; Serine Endopeptidases/genetics
Chemical Substances	Cell Adhesion Molecules, Neuronal ; Extracellular Matrix Proteins ; Nerve Tissue Proteins ; Serine Endopeptidases (EC 3.4.21.-) ; reelin protein (EC 3.4.21.-)
Language	English
Publishing date	2013-07-30
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	445361-x
ISSN	1872-7123 ; 1872-7506 ; 0925-4927 ; 0165-1781
ISSN (online)	1872-7123 ; 1872-7506
ISSN	0925-4927 ; 0165-1781
DOI	10.1016/j.psychres.2012.09.049
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Article ; Online: A balanced translocation truncates Neurotrimin in a family with intracranial and thoracic aortic aneurysm.

Luukkonen, Tiia M / Pöyhönen, Minna / Palotie, Aarno / Ellonen, Pekka / Lagström, Sonja / Lee, Joseph H / Terwilliger, Joseph D / Salonen, Riitta / Varilo, Teppo

Journal of medical genetics

2012 Volume 49, Issue 10, Page(s) 621–629

Abstract: ... a balanced translocation t(10;11) (q23.2;q24.2). Our purpose was to sequence the chromosomal breaks ...

Abstract	Background: Balanced chromosomal rearrangements occasionally have strong phenotypic effects, which may be useful in understanding pathobiology. However, conventional strategies for characterising breakpoints are laborious and inaccurate. We present here a proband with a thoracic aortic aneurysm (TAA) and a balanced translocation t(10;11) (q23.2;q24.2). Our purpose was to sequence the chromosomal breaks in this family to reveal a novel candidate gene for aneurysm. Methods and results: Intracranial aneurysm (IA) and TAAs appear to run in the family in an autosomal dominant manner: After exploring the family history, we observed that the proband's two siblings both died from cerebral haemorrhage, and the proband's parent and parent's sibling died from aortic rupture. After application of a genome-wide paired-end DNA sequencing method for breakpoint mapping, we demonstrate that this translocation breaks intron 1 of a splicing isoform of Neurotrimin at 11q25 in a previously implicated candidate region for IAs and AAs (OMIM 612161). Conclusions: Our results demonstrate the feasibility of genome-wide paired-end sequencing for the characterisation of balanced rearrangements and identification of candidate genes in patients with potentially disease-associated chromosome rearrangements. The family samples were gathered as a part of our recently launched National Registry of Reciprocal Balanced Translocations and Inversions in Finland (n=2575), and we believe that such a registry will be a powerful resource for the localisation of chromosomal aberrations, which can bring insight into the aetiology of related phenotypes.
MeSH term(s)	Actins/genetics ; Aortic Aneurysm, Thoracic/complications ; Aortic Aneurysm, Thoracic/genetics ; Chromosome Breakage ; Chromosome Mapping ; Chromosomes, Human, Pair 10 ; Chromosomes, Human, Pair 11 ; DNA Copy Number Variations ; Family ; Finland ; GPI-Linked Proteins/genetics ; Gene Frequency ; Genes, Dominant ; Genotype ; Humans ; Intracranial Aneurysm/complications ; Intracranial Aneurysm/genetics ; Karyotyping ; Neural Cell Adhesion Molecules/genetics ; Pedigree ; Pilot Projects ; Registries ; Translocation, Genetic
Chemical Substances	ACTA2 protein, human ; Actins ; GPI-Linked Proteins ; Neural Cell Adhesion Molecules ; neurotrimin
Language	English
Publishing date	2012-10-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2012-100977
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Article ; Online: Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population.

Polla, Daniel L / Rahikkala, Elisa / Bode, Michaela K / Määttä, Tuomo / Varilo, Teppo / Loman, Thyrza / Philips, Anju K / Kurki, Mitja / Palotie, Aarno / Körkkö, Jarmo / Vieira, Päivi / Avela, Kristiina / Jacquemin, Valérie / Pirson, Isabelle / Abramowicz, Marc / de Brouwer, Arjan P M / Kuismin, Outi / van Bokhoven, Hans / Järvelä, Irma

European journal of human genetics : EJHG

2019 Volume 27, Issue 8, Page(s) 1235–1243

Abstract: Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one ... ...

Abstract	Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter- and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.
MeSH term(s)	Brain/diagnostic imaging ; Brain/metabolism ; Brain/pathology ; CRADD Signaling Adaptor Protein/genetics ; Family Health ; Female ; Finland ; Founder Effect ; Genetic Predisposition to Disease/genetics ; Geography ; Homozygote ; Humans ; Lissencephaly/diagnostic imaging ; Lissencephaly/genetics ; Lissencephaly/pathology ; Magnetic Resonance Imaging/methods ; Male ; Mutation, Missense ; Pedigree ; Phenotype ; Whole Exome Sequencing
Chemical Substances	CRADD Signaling Adaptor Protein ; CRADD protein, human
Language	English
Publishing date	2019-03-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-019-0383-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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