scholarly journals A Novel Homozygous PKP2 Variant in Severe Neonatal Non-compaction and Concomitant Ventricular Septal Defect: A Case Report

2022 ◽  
Vol 9 ◽  
Author(s):  
Poomiporn Katanyuwong ◽  
Arthaporn Khongkraparn ◽  
Duangrurdee Wattanasirichaigoon
Keyword(s):  
Heart Failure ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Left Ventricular ◽  
Missense Mutations ◽  
Adult Onset ◽  
Autosomal Dominant Disorder ◽  
Aberrant Transcript ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Sarcomeric Genes

Left ventricular non-compaction (LVNC) is a rare and genetically heterogeneous cardiomyopathy. The disorder vastly affects infants and young children. Severe neonatal LVNC is relatively rare. The prevalence of genetic defects underlying pediatric and adult-onset LVNC is about 17–40%. Mutations of MYH7 and MYBPC3 sarcomeric genes are found in the vast majority of the positive pediatric cases. PKP2 encodes plakophilin-2, a non-sarcomeric desmosomal protein, which has multiple roles in cardiac myocytes including cell–cell adhesion, tightening gap junction, and transcriptional factor. Most of the reported PKP2 mutations are heterozygous missense and truncating variants, and they are associated with an adult-onset autosomal dominant disorder, namely arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Homozygous PKP2 mutations have been rarely described. Herein, we present a rare case of an infant with neonatal onset of congestive heart failure owing to severe LVNC and multiple muscular VSD. Medical treatments failed to control the heart failure and the patient died at 11 months of age. Whole-exome sequencing identified a novel homozygous PKP2 variant, c.1511-1G>C, in the patient. An mRNA analysis revealed aberrant transcript lacking exon 7, which was predicted to cause a frameshift and truncated peptide (p.Gly460GlufsTer2). The heterozygous parents had normal cardiac structures and functions as demonstrated by electrocardiogram and echocardiography. Pathogenic variants of sarcomeric genes analyzed were not found in the patient. We conducted a literature review and identified eight families with biallelic PKP2 mutations. We observed that three families (our included) with null variants were linked to lethal phenotypes, while homozygous missense mutations resulted in less severe manifestations: adolescent-onset ARVD/C and childhood-onset DCM. Our data support a previous notion that severe neonatal LVNC might represent a unique entity and had distinct genetic spectrum. In conclusion, the present study has extended the phenotypes and genotypes of PKP2-related disorders and lethal LVNC.

Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients

Cardiology ◽  
2020 ◽  
Vol 145 (11) ◽  
pp. 746-756
Author(s):  
Tatiana Vershinina ◽  
Yulia Fomicheva ◽  
Alexey Muravyev ◽  
John Jorholt ◽  
Alexandra Kozyreva ◽  
...  
Keyword(s):  
Ion Channel ◽  
Age Groups ◽  
Left Ventricular ◽  
Barth Syndrome ◽  
Reduced Ejection Fraction ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Paediatric Patients ◽  
Unknown Significance ◽  
Sarcomeric Genes

<b><i>Introduction:</i></b> Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. <b><i>Patient Group and Methods:</i></b> Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. <b><i>Results:</i></b> The median age at presentation was 8.0 (0.1–17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (<i>ACTN2</i>, <i>MYPN</i>, and <i>TTN</i>) or in metabolic and signal transduction genes (<i>BRAF</i> and <i>TAZ</i>). Likely pathogenic <i>TAZ</i> variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (<i>MYH6</i>, <i>MYH7</i>, and <i>MYLK2</i>). In 4 patients, variants of unknown significance in ion-channel genes were detected. <b><i>Conclusion:</i></b> We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.

scholarly journals A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuan Liu ◽  
Hongke Ding ◽  
Tizhen Yan ◽  
Ling Liu ◽  
Lihua Yu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Dominant Negative ◽  
Facial Features ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Cognitive Delay ◽  
Whole Exome ◽  
Before And After ◽  
Exon Deletion

PACS1 neurodevelopmental disorder (PACS1-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C &gt; T (p.Arg203Trp) and c.608G &gt; A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C &gt; T (p.Arg203Trp) variant.

scholarly journals Human-specific desmoglein 2 mutations in mice models of arrythmogenic right ventricular cardiomyopathy reproduce patients" phenotype

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
D Zankov ◽  
S Ohno
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Mouse Models ◽  
Left Ventricular ◽  
Treadmill Training ◽  
Missense Mutations ◽  
Ventricular Cardiomyopathy ◽  
Human Phenotype ◽  
Cardiac Phenotype ◽  
The Right

Abstract Funding Acknowledgements Type of funding sources: None. Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease that inevitably leads to terminal heart failure and sudden cardiac death due to ventricular arrhythmias. Excessive exercise accelerates the progress of the disease. At present, there is no curative therapy for ARVC. The disease is mostly caused by mutations in genes encoding desmosomal proteins, and Japanese ARVC patients commonly possess missense mutations in DSG2. Although there are animal models with Dsg2-related cardiomyopathy, they do not reflect the precise human disease caused by missense mutations in DSG2. Purpose We aimed to generate knock-in mouse models of ARVC carrying Dsg2 mutations equivalent to those found in ARVC patients. Methods We introduced Dsg2 mutations (R297C, D499A), which were equivalent to most common mutations in Japanese ARVC patients, to mice by CRSPR/Cas9 genome editing system. Echocardiography and treadmill training were performed to evaluate the cardiac phenotype of the mouse models. Results There is phenotype inequality between the two lines of Dsg2 knock-in mice. In R297C mice, all the homozygotes died suddenly until the age of 20 weeks, and half of the heterozygotes until the age of 25 weeks. Heart examination of the deceased homozygous mice demonstrated enlarged cavities, predominantly in the right ventricles, and scattered pale patches suggesting fibrotic replacement of the myocardium. Echocardiography of four 9-week-old homozygous mice shows acoustically dense zones (white arrows in the left figure) and left ventricular dysfunction (ejection fraction (EF) &lt; 35%). Exploration of the hearts of sacrificed mice confirmed echocardiographical findings (red arrow in the right figure) demonstrating scattered pale regions similar to those in suddenly died mice. In contrast, homozygous and heterozygous D499A mice survived without sudden death. Both mutant mice develop heart failure after the age of 30 weeks. To mimic the effect of exercise, we performed treadmill training for two months started from 11 weeks old in both types of D499A and heterozygous R297C mice. The training significantly accelerated cardiac dysfunction: all D499A mice (homo and hetero) and half of heterozygous R297C developed biventricular dysfunction at the age of 19 weeks though no change in WT. EF for R297C heterozygous mice, D499A heterozygous and D499A homozygous mice decreased from 64.4 ± 4.3%, 71.9 ± 1.7% and 73.9 ± 1.1 to 31.2 ± 5.7%, 16.6 ± 2.1% and 12.4%±1.9, respectively. Treadmill training did not alter significantly EF in WT mice: 71.8 ± 2.3% before and 67.5 ± 1.4 at the end of physical challenge. Conclusion We generated mouse model of ARVC mutations that mimic the exact gene defect found in the humans. Our experimental work confirms significant overlap to the human phenotype. Further investigation will clarify the underlying cellular mechanisms. Abstract Figure. A heart from homozygous R297C mouse

scholarly journals Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Metaphyseal Chondrodysplasia ◽  
Whole Exome ◽  
Col10a1 Gene ◽  
Silico Analysis ◽  
Nc1 Domain

Abstract Background: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 normal control donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results: We found that the phenotype of affected family members exhibited irregular dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion: Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of irregular dominance in MCDS.

scholarly journals Combination of Arrhythmogenic Right Ventricular Dysplasia with Left Ventricular Non-Compaction as a Special Form of Cardiomyopathy: Clinic, Diagnostics, Genetic, Natural Course

2020 ◽  
Vol 75 (6) ◽  
pp. 594-604
Author(s):  
Yu. A. Lutokhina ◽  
O. V. Blagova ◽  
A. G. Shestak ◽  
M. Е. Polyak ◽  
A. A. Bukaeva ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Left Ventricular ◽  
Pathogenic Variants ◽  
Right Ventricular Dysplasia ◽  
Therapy Effect ◽  
Appropriate Shocks ◽  
Gene Panels ◽  
Electrocardiogram Ecg

Background. A few cases of combination of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) with left ventricular noncompaction (LVNC) have been described. Aims to study the genetics, diagnostical features and clinical course of the combination of ARVC with LVNC. Methods. 58 patients with ARVC diagnosis (26 men; mean age 39.1 14.2 years; mean follow-up period 21.5 [6; 60] months) and 125 patients with LVNC (74 men; mean age 46.4 15.1 years; mean follow-up period 14 [3; 40] months). All patients underwent electrocardiogram (ECG), echocardiography, 24-h ECG monitoring. Heart MRI was performed in 53 (91.4%) patients with ARVC and 60 (48%) with LVNC, heart CT in 18 (31%) patients with ARVC and 89 (71.2%) with LVNC. For all patients with combination of ARVC and LVNC DNA-diagnostic was performed using both ARVC (PKP2, DSG2, DSP, DSC2, JUP, TMEM43, TGFB3, PLN, LMNA, DES, CTTNA3, EMD, SCN5A, LDB3, CRYAB, FLNC) and LVNC (MYH7, MYBPC3, TAZ, TPM1, LDB3, MYL2, MYL3, ACTC1, TNNT2, TNI3) gene panels. Results. Combination of ARVC and LVNC was found in 9 patients (15.5% of patients form ARVC cohort and 7.2% from LVNC cohort). These patients were distinguished from patients with isolated ARVC or LVNC by aggressive ventricular arrhythmias (frequent premature ventricular beats, sustained ventricular tachycardia, significantly worse antiarrhythmic therapy effect, appropriate shocks of implanted cardioverter-defibrillators (ICD) in all patients with ICD). Patients with combination of ARVC + LVNC were also distinguished from patients with isolated LVNC by the dilatation of RV, low QRS voltage on ECG, presence of AV block, absence of signs of LV hypertrophy on ECG. LV dilatation with reduction of its ejection fraction distinguished patients with mixed cardiomyopathy from patients with isolated ARVC. Potentially pathogenic variants (IVV classes of pathogenicity) and variants of unclear clinical significance (III class of pathogenicity) were found in both desmosomal and non-desmosomal genes in 78% of patients, including 3 (33%) in DSP gene. Conclusions. The combination of ARVC and LVNC can be caused by mutations in both desmosomal and non-desmosomal genes and has typical features: aggressive, resistant ventricular rhythm abnormalities leading to appropriate ICD shocks and a high risk of sudden cardiac death.

scholarly journals Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (DSP)

2022 ◽  
Vol 12 (1) ◽  
pp. 24-36
Author(s):  
Nosheen Reza ◽  
Alejandro de Feria ◽  
Jessica L. Chowns ◽  
Lily Hoffman-Andrews ◽  
Laura Vann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Genetic Variation ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
University Of Pennsylvania ◽  
Initial Assessment ◽  
Clinical Genetic ◽  
Pathogenic Variants ◽  
End Stage

Background: Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC. Methods: We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovascular Disease registry. We performed a retrospective study of 19 individuals with “pathogenic” or “likely pathogenic” variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected. Results: Among individuals with disease-causing variants in DSP, nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were prevalent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%). Conclusions: Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated.

scholarly journals RYR2 Mutations Are Associated With Benign Epilepsy of Childhood With Centrotemporal Spikes With or Without Arrhythmia

2021 ◽  
Vol 15 ◽  
Author(s):  
Mei-Gang Ma ◽  
Xiao-Rong Liu ◽  
Yuan Wu ◽  
Jie Wang ◽  
Bing-Mei Li ◽  
...  
Keyword(s):  
De Novo ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Polymorphic Ventricular Tachycardia ◽  
Compound Heterozygous ◽  
Endoplasmic Reticulum Membrane ◽  
Missense Mutations ◽  
Unexpected Death ◽  
Sinus Arrhythmia ◽  
Whole Exome ◽  
Benign Epilepsy

RYR2 encodes ryanodine receptor 2 protein (RYR-2) that is mainly located on endoplasmic reticulum membrane and regulates intracellular calcium concentration. The RYR-2 protein is ubiquitously distributed and highly expressed in the heart and brain. Previous studies have identified the RYR2 mutations in the etiology of arrhythmogenic right ventricular dysplasia 2 and catecholaminergic polymorphic ventricular tachycardia. However, the relationship between RYR2 gene and epilepsy is not determined. In this study, we screened for novel genetic variants in a group of 292 cases (families) with benign epilepsy of childhood with centrotemporal spikes (BECTS) by trio-based whole-exome sequencing. RYR2 mutations were identified in five cases with BECTS, including one heterozygous frameshift mutation (c.14361dup/p.Arg4790Pro fs∗6), two heterozygous missense mutations (c.2353G &gt; A/p.Asp785Asn and c.8574G &gt; A/p.Met2858Ile), and two pairs of compound heterozygous mutations (c.4652A &gt; G/p.Asn1551Ser and c.11693T &gt; C/p.Ile3898Thr, c.7469T &gt; C/p.Val2490Ala and c.12770G &gt; A/p.Arg4257Gln, respectively). Asp785Asn was a de novo missense mutation. All the missense mutations were suggested to be damaging by at least three web-based prediction tools. These mutations do not present or at low minor allele frequency in gnomAD database and present statistically higher frequency in the cohort of BECTS than in the control populations of gnomAD. Asp785Asn, Asn1551Ser, and Ile3898Thr were predicted to affect hydrogen bonds with surrounding amino acids. Three affected individuals had arrhythmia (sinus arrhythmia and occasional atrial premature). The two probands with compound heterozygous missense mutations presented mild cardiac structural abnormalities. Strong evidence from ClinGen Clinical Validity Framework suggested an association between RYR2 variants and epilepsy. This study suggests that RYR2 gene is potentially a candidate pathogenic gene of BECTS. More attention should be paid to epilepsy patients with RYR2 mutations, which were associated with arrhythmia and sudden unexpected death in previous reports.

scholarly journals When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1636
Author(s):  
Camille Cenni ◽  
Luke Mansard ◽  
Catherine Blanchet ◽  
David Baux ◽  
Christel Vaché ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Case Report ◽  
De Novo ◽  
Panel Analysis ◽  
Adult Onset ◽  
Childhood Onset ◽  
Model Case ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Neonatal Thrombocytopenia

We describe a family with both hearing loss (HL) and thrombocytopenia, caused by pathogenic variants in three genes. The proband was a child with neonatal thrombocytopenia, childhood-onset HL, hyper-laxity and severe myopia. The child’s mother (and some of her relatives) presented with moderate thrombocytopenia and adulthood-onset HL. The child’s father (and some of his relatives) presented with adult-onset HL. An HL panel analysis, completed by whole exome sequencing, was performed in this complex family. We identified three pathogenic variants in three different genes: MYH9, MYO7A and ACTG1. The thrombocytopenia in the child and her mother is explained by the MYH9 variant. The post-lingual HL in the paternal branch is explained by the MYO7A variant, absent in the proband, while the congenital HL of the child is explained by a de novo ACTG1 variant. This family, in which HL segregates, illustrates that multiple genetic conditions coexist in individuals and make patient care more complex than expected.

scholarly journals Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Lingchi Kong ◽  
Li Shi ◽  
Wenbo Wang ◽  
Rongtai Zuo ◽  
Mengwei Wang ◽  
...  
Keyword(s):  
Family Members ◽  
In Silico Analysis ◽  
Coxa Vara ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Incomplete Dominance ◽  
Metaphyseal Chondrodysplasia ◽  
Whole Exome ◽  
Healthy Donors ◽  
Nc1 Domain

Abstract Background Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results We found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765 T > A (p.Phe589Ile)] and [c.1846A > G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.

scholarly journals Phenotypic and Molecular Spectrum of Patients With Switch/sucrose Nonfermenting Complex-related Intellectual Disabilities in Korea

2021 ◽  
Author(s):  
Yena Lee ◽  
Yunha Choi ◽  
Go Hun Seo ◽  
Gu-Hwan Kim ◽  
Changwon Keum ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disorder ◽  
Missense Mutations ◽  
Speech Delay ◽  
Dna Accessibility ◽  
Pathogenic Variants ◽  
Disease Spectrum ◽  
Whole Exome ◽  
Altered Gene ◽  
Spectrum Of Patients

Abstract Background: The switch/sucrose nonfermenting (SWI/SNF) complex is an adenosine triphosphate (ATP)-dependent chromatin-remodeling complex associated with the regulation of DNA accessibility. Germline mutations in the components of the SWI/SNF complex are related to human developmental disorder, including the Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. These disorders are collectively referred to as SWI/SNF-related intellectual disability (SSRIDD).Methods: Whole exome sequencing was performed in 564 Korean patients with neurodevelopmental disorders. Twelve patients with SSRIDDs (2.1%) were included, and their medical records were retrospectively analyzed. Results: ARID1B, found in eight patients, were the most frequently-altered gene. Four patients harbored mutations in SMARCA4, SMARCB1, ARID2, and SMARCA2. Ten patients were diagnosed with CSS, and one patient without typical phenotypes was classified as ARID1B-related intellectual disability. Another patient harboring the SMARCA2 mutation was diagnosed with NCBRS. All pathogenic variants in ARID1B were truncating, whereas variants in SMARCA2, SMARCB1, and SMARCA4 were nontruncating (missense) mutations. Frequently-observed phenotypes were thick eyebrows (10/12), hypertrichosis (8/12), coarse face (8/12), thick lips (8/12), and long eyelashes (8/12). Developmental delay was observed in all patients, and profound speech delay was also characteristic. Agenesis or hypoplasia of the corpus callosum was found in half of the patients (6/12).Conclusions: SSRIDD holds a broad disease spectrum, including NCBRS, CSS, and ARID1B-related intellectual disability. Thus, the SSRIDD should be considered as a small but important cause of human developmental disorder.

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