Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease.

Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.

Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype.

BACKGROUND: Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types. METHODS: We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects. RESULTS: A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers. CONCLUSIONS: The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.

Wilson's Disease in Finland: A Nationwide Population-Based Study.

BACKGROUND: Data on the epidemiology and prognosis of Wilson's disease are scarce, and no clinical data are available from Finland. METHODS: All persons diagnosed and treated for Wilson's disease in Finnish hospitals in 1998 to 2017 were identified. Data were collected from national registries and patient charts. RESULTS: The point prevalence was 0.45/100,000 (95% confidence interval, 0.29-0.67) on December 31, 2017, but no more than 0.35/100,000 (95% confidence interval, 0.21-0.55) among native Finns. Annual incidence was 0.016/100,000 (95% confidence interval, 0.0093-0.026). Median age at diagnosis was 15.8 years (interquartile range, 8.3-32.2; range, 3.8-48.1 years). Upon presentation, liver damage was observed in 58%, neurological signs and symptoms (most often tremor and dysarthria) in 40%, and 32% of patients were asymptomatic. Patients had poorer long-term survival (hazard ratio, 2.92 for death; P = 0.005) compared with matched controls. CONCLUSIONS: Wilson's disease is very rare in Finland. Patients have an increased risk of death indicating an unmet treatment need. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A 69-year-old woman with Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS) is a rare intellectual disability syndrome classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and other digits, distinctive facial features, hirsutism/hypertrichosis, and sparce scalp hair. It is genetically heterogeneous but most often caused by a pathogenic variant in the ARID1B gene. Previous clinical reports of CSS patients are mainly based on young or middle-aged individuals. Here, we report a 69-year-old woman with CSS phenotype and a pathogenic ARID1B loss-of-function variant c.5259_5260dup. She has severe intellectual disability but otherwise she is in relatively good health both physically and mentally. There is no evident history of chronic illness or progressive disability. CSS appears to be compatible with long survival and most likely it is underdiagnosed in geriatric patients with intellectual disability.

TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae. © 2017 Wiley Periodicals, Inc.

PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome.

Recently, mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor have been identified in a new subclass of congenital disorders of glycosylation (CDGs) with a distinct spectrum of clinical features. To date, mutations have been identified in six genes (PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV) encoding proteins in the GPI-anchor-synthesis pathway in individuals with severe neurological features, including seizures, muscular hypotonia, and intellectual disability. We developed a diagnostic gene panel for targeting all known genes encoding proteins in the GPI-anchor-synthesis pathway to screen individuals matching these features, and we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T, in two unrelated individuals with hyperphosphatasia with mental retardation syndrome (HPMRS). The mutations cosegregated in the investigated families. PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus and is required for stable association between GPI-anchored proteins and the cell-surface membrane rafts. Transfection of the altered protein constructs, p.Arg16Trp (NP_001243169.1), p.Leu127Ser, and p.Thr160Ile, into PGAP2-null cells showed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface. In this work, we show that an impairment of GPI-anchor remodeling also causes HPMRS and conclude that targeted sequencing of the genes encoding proteins in the GPI-anchor-synthesis pathway is an effective diagnostic approach for this subclass of CDGs.

Primary mediastinal large B-cell lymphoma segregating in a family: exome sequencing identifies MLL as a candidate predisposition gene.

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) accounting for 2% to 4% of all non-Hodgkin lymphomas. We report a family of 3 siblings with PMBCL and their cousin with extranodal DLBCL. The histopathological characteristics of lymphomas of all 4 patients are similar, implying post-germinal center differentiation and growth deregulation by other mechanisms than BCL2-mediated inhibition of apoptosis and suggesting a shared biological background. We aimed to identify the genetic defect underlying lymphoma susceptibility in this family using exome sequencing and linkage analysis. The only variant segregating in all 4 patients and not reported in genetic databases was 5533C>A (His1845Asn) in the MLL gene. To our knowledge, this is the first time when familial clustering of PMBCL is reported. Although we propose MLL as a candidate predisposition gene for this condition, this finding needs to be validated in additional cases.

[Parkinson's disease associated with a mutation in the PARK2 gene]. / PARK2-geenin mutaatioon liittyvä Parkinsonin tauti.

The most common cause of monogenic hereditary Parkinson's disease is a mutation in the PARK2 gene. Early onset, slow progression, dystonia, and good response to levodopa are typical of the disease phenotype. Finnish PARK2 patients have not been described previously. We describe two patients, in whom pathogenic mutations in the PARK2 gene were the cause of parkinsonism.

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.

Overlap between EEC and AEC syndrome and immunodeficiency in a preterm infant with a TP63 variant.

Pathogenic variants in the transcription factor TP63 gene cause a variety of clinical phenotypes, such as ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome and ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome. Historically, TP63-related phenotypes have been divided into several syndromes based on both the clinical presentation and location of the pathogenic variant on the TP63 gene. This division is complicated by significant overlap between syndromes. Here we describe a patient with clinical characteristics of different TP63-associated syndromes (cleft lip and palate, split feet, ectropion, erosions of the skin and corneas), associated with a de novo heterozygous pathogenic variant c.1681 T>C, p.(Cys561Arg) in exon 13 of the TP63 gene. Our patient also developed enlargement of the left-sided cardiac compartments and secondary mitral insufficiency, which is a novel finding, and immune deficiency, which has only rarely been reported. The clinical course was further complicated by prematurity and very low birth weight. We illustrate the overlapping features of EEC and AEC syndrome and multidisciplinary care needed to address the various clinical challenges.

Exploring the transcriptomic variation caused by the Finnish founder mutation of lysinuric protein intolerance (LPI).

Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by mutations in cationic amino acid transporter gene SLC7A7. Although all Finnish patients share the same homozygous mutation, their clinical manifestations vary greatly. The symptoms range from failure to thrive, protein aversion, anemia and hyperammonaemia, to immunological abnormalities, nephropathy and pulmonary alveolar proteinosis. To unravel the molecular mechanisms behind those symptoms not explained directly by the primary mutation, gene expression profiles of LPI patients were studied using genome-wide microarray technology. As a result, we discovered 926 differentially-expressed genes, including cationic and neutral amino acid transporters. The functional annotation analysis revealed a significant accumulation of such biological processes as inflammatory response, immune system processes and apoptosis. We conclude that changes in the expression of genes other than SLC7A7 may be linked to the various symptoms of LPI, indicating a complex interplay between amino acid transporters and various cellular processes.

High-resolution SNP array analysis of patients with developmental disorder and normal array CGH results.

BACKGROUND: Diagnostic analysis of patients with developmental disorders has improved over recent years largely due to the use of microarray technology. Array methods that facilitate copy number analysis have enabled the diagnosis of up to 20% more patients with previously normal karyotyping results. A substantial number of patients remain undiagnosed, however. METHODS AND RESULTS: Using the Genome-Wide Human SNP array 6.0, we analyzed 35 patients with a developmental disorder of unknown cause and normal array comparative genomic hybridization (array CGH) results, in order to characterize previously undefined genomic aberrations. We detected no seemingly pathogenic copy number aberrations. Most of the vast amount of data produced by the array was polymorphic and non-informative. Filtering of this data, based on copy number variant (CNV) population frequencies as well as phenotypically relevant genes, enabled pinpointing regions of allelic homozygosity that included candidate genes correlating to the phenotypic features in four patients, but results could not be confirmed. CONCLUSIONS: In this study, the use of an ultra high-resolution SNP array did not contribute to further diagnose patients with developmental disorders of unknown cause. The statistical power of these results is limited by the small size of the patient cohort, and interpretation of these negative results can only be applied to the patients studied here. We present the results of our study and the recurrence of clustered allelic homozygosity present in this material, as detected by the SNP 6.0 array.

Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome with cutaneous and uterine leiomyomatosis as well as renal cell cancer (RCC) as its clinical manifestations. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (fumarase) gene. In this study, we used array comparative genomic hybridization to identify the specific copy number changes characterizing the HLRCC-associated RCCs. The study material comprised formalin-fixed paraffin-embedded renal tumors obtained from Finnish patients with HLRCC. All 11 investigated tumors displayed the papillary type 2 histopathology typical for HLRCC renal tumors. The most frequent copy number changes detected in at least 3/11 (27%) of the tumors were gains in chromosomes 2, 7, and 17, and losses in 13q12.3-q21.1, 14, 18, and X. These findings provide genetic evidence for a distinct copy number profile in HLRCC renal tumors compared with sporadic RCC tumors of the same histopathological subtype, and delineate chromosomal regions that associate with this very aggressive form of RCC.

Genitopatellar syndrome in an adolescent female with severe osteoporosis and endocrine abnormalities.

Genitopatellar syndrome (GPS) is a rare disorder with characteristic craniofacial features, congenital flexion contractures of the lower limbs, absent or abnormal patellae, urogenital anomalies, and severe psychomotor retardation. Twelve patients with ages from 15 days to 12 years and two affected fetuses have been reported. We describe a 17-year-old female with a phenotype consistent with GPS. Being the oldest reported patient, she is the first one showing severe symptomatic osteoporosis and endocrine abnormalities including primary hypothyroidism and delayed puberty. We suggest that these novel findings are also manifestations of GPS.

Are patient rights to information and self-determination in diagnostic genetic testing upheld? A comparison of patients' and providers' perceptions.

This study assessed how the patient's right to receive information and the right to self-determination were followed during diagnostic testing, according to the perceptions of patients and parents of tested children (group 1, n = 106) and healthcare personnel (group 2, n = 162). Data were collected in three Finnish university hospitals using a questionnaire. Results revealed one between group difference: patients/parents agreed more strongly than did personnel that self-determination was followed before testing. Within groups included: patients/parents had stronger agreement that self-determination was followed before testing than after testing; personnel had stronger agreement about information received after testing than before testing, and they had weaker agreement about how well self-determination was followed before testing than after testing. Received information was experienced as similar both before and after testing and by patients/parents and by personnel. Providing adequate time to consider whether or not to be tested and giving more support to patients after testing would promote the rights of patients. Furthermore, assessment of personnel characteristics is needed to determine, for example, the kinds of value conflicts that exist between personnel's own values and patients' values.

HTT haplogroups in Finnish patients with Huntington disease.

OBJECTIVE: To study genetic causes of the low frequency of Huntington disease (HD) in the Finnish population, we determined HTT haplogroups in the population and patients with HD and analyzed intergenerational Cytosine-Adenosine-Guanosine (CAG) stability. METHODS: A national cohort of patients with HD was used to identify families with mutant HTT (mHTT). HTT haplogroups were determined in 225 archival samples from patients and from 292 population samples. CAG repeats were phased with HTT haplotypes using data from parent-offspring pairs and other mHTT carriers in the family. RESULTS: The allele frequencies of HTT haplotypes in the Finnish population differed from those in 411 non-Finnish European subjects (p < 0.00001). The frequency of haplogroup A was lower than that in Europeans and haplogroup C was higher. Haplogroup A alleles were significantly more common in patients than in controls. Among patients with HD haplotypes A1 and A2 were more frequent than among the controls (p = 0.003). The mean size of the CAG repeat change was +1.38 units in paternal transmissions being larger than that (-0.17) in maternal transmissions (p = 0.008). CAG repeats on haplogroup A increased by 3.18 CAG units in paternal transmissions, but only by 0.11 units in maternal transmissions (p = 0.008), whereas haplogroup C repeat lengths decreased in both paternal and maternal transmissions. CONCLUSIONS: The low frequency of HD in Finland is partly explained by the low frequency of the HD-associated haplogroup A in the Finnish population. There were remarkable differences in intergenerational CAG repeat dynamics that depended on HTT haplotype and parent gender.

Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.

What is ideal genetic counselling? A survey of current international guidelines.

The objective of this article is to review guidelines that address counselling in the context of genetic testing in order to summarise what aspects of counselling they consider most important, and to examine how they construct the ideal of genetic counselling. Guidelines were collected by examining the websites of different international professional, political, ethical and patient organisations, either previously known or found with the help of the Google search engine, and also using references listed in other studies. The most frequently mentioned topics in the collected 56 guidelines were sought, and this was carried out with the software package Qualitative Solutions and Research for Non-numerical Unstructured Data Indexing Searching and Theorizing. Topics related to genetic counselling that were mentioned in at least 30 of 56 collected documents were considered to be the most important aspects of genetic counselling. The ideal of genetic counselling is expressed in the analysed guidelines as being composed of (1) an appropriately trained professional who understands genetics and its ethical implications well; (2) relevant and objective information; (3) assurance of the counsellee's understanding; (4) psychological support; (5) informed consent; (6) confidentiality of genetic information; (7) considering familial implications; (8) appropriate handling of potential discrimination of testing; and (9) assuring autonomous decision-making by the counsellee. The ideal of genetic counselling is rather consistent in the guidelines, but there are some contradictions between the requirements of objective information-giving and adapting counselling to counsellee's circumstances.

Regulations and practices of genetic counselling in 38 European countries: the perspective of national representatives.

The aim of this article is to review the national regulations and practices of genetic counselling in 38 European countries, and to examine how well they intersect the ideals of genetic counselling defined in international guidelines. Using an electronic survey, representatives of the National Societies of Human Genetics in 29 countries, and appropriate contact persons for the field of genetic counselling in 9 other countries, were asked about the regulations and practices. The answers showed that consent, confidentiality, genetic counselling in the context of prenatal diagnosis, those professionals who may perform genetic counselling, and non-directiveness were the topics most often either agreed upon among professionals or regulated in those countries. These are also among the key aspects of ideal genetic counselling, based on international guidelines. Counselling in the context of susceptibility testing for multifactorial diseases, counselling people from ethnic minorities and recontacting the counsellees, on the contrary, were topics regulated or guided by generally applied practices in only few countries. Many of the answers expressed a desire for more regulation of genetic counselling, and that more uniform practices of education and organization of genetic counselling would be welcome in Europe.