Familial Phonological Disorders

1990 ◽  
Vol 55 (1) ◽  
pp. 160-170 ◽  
Author(s):  
Barbara A. Lewis
Keyword(s):  
Learning Disabilities ◽  
Autosomal Dominant ◽  
Threshold Model ◽  
Family Members ◽  
Speech Disorders ◽  
Dominant Mode ◽  
Incomplete Penetrance ◽  
Phonological Disorders ◽  
Language Problems ◽  
Mode A

The pedigrees of 4 children with a severe phonological disorder demonstrating three generations of members with speech/language problems are presented. All 4 probands were female with two mothers, two fathers, and five out of six siblings affected. All pedigrees contained family members with dyslexia and learning disabilities as well as speech disorders. Family members varied in the type of speech problems that they demonstrated and the severity of their disorder, thus suggesting variable expressivity and incomplete penetrance. An autosomal dominant mode, a multifactorial-polygenic model, and a sex-specific threshold model for expression are discussed.

scholarly journals Clinical and genetic analysis of Ser341Pro MYOC variant in a Korean family with primary open angle glaucoma

2020 ◽  
Vol 13 (11) ◽  
pp. 1689-1696
Author(s):  
Sangwoo Moon ◽  
◽  
Namhee Kim ◽  
Jiwoong Lee ◽  
◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Normal Population ◽  
Direct Sequencing ◽  
Family Members ◽  
Poor Response ◽  
Clinical Aspects ◽  
Incomplete Penetrance ◽  
Open Angle

AIM: To report the first discovery of Ser341Pro myocilin (MYOC) variant in Korea and analyze its clinical characteristics and genetic significance. METHODS: Ten family members from three generations participated in this study and received the thorough ophthalmologic examination. Focused exome sequencing on a proband was performed to confirm the target mutations (MYOC c.1021T>C) in the family members, and the direct sequencing was conducted. Variant was analyzed according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: A nucleotide change from thymine to cytosine at c.1021T>C was found in eight family members. Three members diagnosed with primary open angle glaucoma (POAG) were characterized by severe clinical presentations, high intraocular pressure, and poor response to medical treatment (100% of the patient required filtering surgery). On variant analysis by ACMG/AMP guidelines, Ser341Pro is not found in normal population. Multiple computational predictive programs support a deleterious effect of Ser341Pro variant (PolyPhen 2, SIFT, Mutation Taster). Ser341Pro could be involved in moderate (PM) and supporting (PP) criteria (PM1, PM2, PP2, PP3). Combining the criteria, Ser341Pro has a combination of 2 moderate (PM1+PM2) and 2 supporting (PP2+PP3) criteria, which is interpreted to “likely pathogenic”. CONCLUSION: The Ser341Pro variant is correlated with severe phenotype of POAG. There are similar clinical aspects to previous studies: autosomal dominant inheritance, incomplete penetrance (62.50% and 66.67%), and proportion of patients requiring trabeculectomy (100% in both study). According to ACMG/AMP guidelines and the previous basic researches, the Ser341Pro variant had a “strong evidence of pathogenicity (PS3)” and then it could be interpreted to “pathogenic (PS3, PM1, PM2, PP2, PP3)”. Additionally, Ser341Pro variant can be reported as “c.1021T>C (p.Ser341Pro), likely pathogenic, POAG, autosomal dominant” according to guideline.

scholarly journals c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa-responsive dystonia

2017 ◽  
Vol 3 (6) ◽  
pp. e197 ◽  
Author(s):  
Ali S. Shalash ◽  
Thomas W. Rösler ◽  
Stefanie H. Müller ◽  
Mohamed Salama ◽  
Günther Deuschl ◽  
...  
Keyword(s):  
High Performance ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
Synergistic Effects ◽  
Family Members ◽  
Incomplete Penetrance ◽  
Sepiapterin Reductase ◽  
Variant Filtering ◽  
Exon 1 ◽  
Functional Consequences

Objective:To elucidate the genetic cause of an Egyptian family with dopa-responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes.Methods:Rare variants in all coding exons ofGCH1were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography.Results:A heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (SPR, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in mostSPRmutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (DHFR, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only.Conclusions:The rareSPRmutation can cause autosomal dominant DRD with incomplete penetrance. The commonDHFRvariant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance.

scholarly journals A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 454 ◽  
Author(s):  
Petra Hug ◽  
Linda Anderegg ◽  
Nicole Dürig ◽  
Vincent Lepori ◽  
Vidhya Jagannathan ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Dominant Mode ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Reading Frame ◽  
Eye Disorders ◽  
Residual Amount ◽  
Homeobox Transcription Factor ◽  
The Common ◽  
Close Relatives

Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs.

scholarly journals A novel missense mutation of GJA8 causes congenital cataract in a large Mauritanian family

2018 ◽  
Vol 29 (6) ◽  
pp. 621-628 ◽  
Author(s):  
Mouna Hadrami ◽  
Crystel Bonnet ◽  
Fatimetou Veten ◽  
Christina Zeitz ◽  
Christel Condroyer ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Family Members ◽  
Dominant Mode ◽  
Wild Type ◽  
New Mutation ◽  
The Family ◽  
History Of ◽  
Eye Examination ◽  
Generation Sequencing

Objective of the study: Inborn lens opacity is the most frequent cause of childhood blindness. In this study, we aimed to define the presumed genetic cause of a congenital cataract present in a Mauritanian family over the last nine generations. Methods: A family history of the disease and eye examination were carried out for the family members. Next-generation sequencing using a panel of 116 cataract underlying genes was selectively conducted on the proband’s DNA. Nucleotide and amino acid changes and their impact on the phenotype were evaluated using various data analyzing software. Results: Congenital nuclear cataract, with autosomal dominant mode, was observed in the family. All patients had consequences on their vision in the first 2 years of life. Genetic screening revealed a new mutation c.166A>C (p.Thr56Pro) in GJA8, encoding the Cx50 α-connexin protein. This mutation co-segregated in all patients and was not observed in the unaffected family members and controls. The predicted secondary structure impacted by p.Thr56Pro revealed a localized disruption, in the first extra membrane loop of the wild-type sheet, which is replaced in the mutant protein by a turn then a coil. This conformational change was functionally predicted as probably damaging. Conclusion: A new mutation (c.166A>C) in GJA8 underlying a nuclear congenital cataract was identified in this study. Its segregation with the phenotype might be useful as a predicting marker of the disease.

The Speech-Language Pathologists’s Role in Understanding the Genetics of Van Der Woude Syndrome

1979 ◽  
Vol 44 (4) ◽  
pp. 472-478 ◽  
Author(s):  
Lillian Glass ◽  
Ray E. Stewart ◽  
Judith Miles
Keyword(s):  
Family History ◽  
Cleft Lip ◽  
Family Members ◽  
Pedigree Analysis ◽  
Speech Disorders ◽  
Incomplete Penetrance ◽  
Van Der Woude Syndrome ◽  
Variable Expression ◽  
Speech Language Pathologist ◽  
Previous Diagnosis

A family report of three generations of Van der Woude syndrome (cleft lip or palate and lip pits) is presented to show that the speech-language pathologist may play an important role in identifying patients with this defect. Understanding the genetic basis of this syndrome and documentation of family history through pedigree analysis can be instrumental in identifying other family members potentially affected with speech disorders. Because the diagnosis of Van der Woude syndrome was made in one member of the family in the pedigree, three other family members who had never received previous diagnosis or treatment of their speech disorders were identified. Other family members were referred for genetic counseling. The concepts of autosomal dominant transmission, variable expression, incomplete penetrance, and the pedigree technique for recording family history are also presented.

scholarly journals A mutated CRYGD associated with congenital coralliform cataracts in two Chinese pedigrees

2021 ◽  
Vol 14 (6) ◽  
pp. 800-804
Author(s):  
Su-Ping Cai ◽  
◽  
Xi-Zhen Wang ◽  
Yun Wang ◽  
Fen He ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Family Members ◽  
Dominant Mode ◽  
Heterozygous Mutation ◽  
Sequencing Analysis ◽  
Causal Gene ◽  
Exon 2 ◽  
Coding Regions ◽  
Coralliform Cataract

AIM: To investigate the causal gene mutation and clinical characteristics for two Chinese families with autosomal dominant congenital coralliform cataract. METHODS: Two Chinese pedigrees with congenital cataract were investigated. Routine ophthalmic examinations were performed on all patients and non-affected family members. Peripheral blood samples were collected, and the genomic DNAs were extracted. The coding regions of proband’s DNAs were analyzed with cataract gene panel. The identified mutation was amplified by polymerase chain reaction, and automated sequencing was performed in other members of two families to verify whether the mutated gene was co-segregated with the disease. RESULTS: Congenital coralliform cataract was inherited in an autosomal dominant mode in both pedigrees. For each family, more than half of the family members were affected. All patients presented with severe visual impairment after birth as a result of bilateral symmetric coralliform lens opacification. An exact the same defect in the same gene, a heterozygous mutation of c.70C>A (p. P24T) in exon 2 of γD-crystallin gene, was detected in both probands from each family. Sanger sequencing analysis demonstrated that the mutated CRYGD was co-segregated in these two families. CONCLUSION: A c.70C>A (p. P24T) variant in CRYGD gene was reconfirmed to be the causal gene in two Chinese pedigrees. It is known that mutated CRYGD caused most of the congenital coralliform cataracts, suggesting that the CRYGD gene is associated with coralliform congenital cataract.

Abstract 198: Familial Hypercholesterolemia and Intra-Cranial Aneurysm: A Novel Phenotypic and Genetic Association

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Arvind K Pandey ◽  
Jason R Becker
Keyword(s):  
Familial Hypercholesterolemia ◽  
Intracranial Aneurysms ◽  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Low Density Lipoprotein ◽  
Family Members ◽  
Density Lipoprotein ◽  
Pedigree Analysis ◽  
Dominant Mode ◽  
Illumina Hiseq

Background: Autosomal dominant familial hypercholesterolemia (FH) is characterized by elevated levels of low density lipoprotein (LDL) cholesterol. Mutations in LDLR, APOB, and PCSK9 genes are established causes of this condition. However, in up to 20-40% of cases, the genetic cause has not been defined. FH is associated with coronary ectasias, but extra-cardiac vascular malformations have not been described. Methods: A subject with hypercholesterolemia was evaluated, and a three generation pedigree was constructed. Whole exome sequencing (WES) was performed (Illumina HiSeq 2500, 100x avg coverage) and reads were aligned to a human reference genome (hg19) using BWA. Variants were called with GATK Unified Genotyper and annotated using SeattleSeq. Results: Pedigree analysis suggested an autosomal dominant mode of inheritance of the hypercholesterolemia trait (Fig 1). Multiple family members also had intracranial aneurysms. Targeted analysis of the classical genes associated with FH (LDLR, APOB, and PCSK9) did not identify any missense, nonsense, or splice site variants with a minor allele frequency (MAF) < 0.01. Expanded analysis of the entire exome yielded rare missense variants (MAF < 0.001) in 845 genes and nonsense variants in 22 genes. Conclusions: Utilizing WES we rapidly screened an individual for pathogenic DNA variants in genes previously associated with FH. The genetic factor underlying our patient’s FH appears to be distinct from the known causes of FH. Genetic analysis of additional family members will be necessary to define the novel genetic cause of FH in this pedigree and explore the relationship of intracranial aneurysms with FH.

Genetic Characterization of Familial CPVT After 30 Years

2009 ◽  
Vol 11 (1) ◽  
pp. 66-72 ◽  
Author(s):  
Theresa A. Beery ◽  
Maully J. Shah ◽  
D. Woodrow Benson
Keyword(s):  
Ventricular Tachycardia ◽  
Autosomal Dominant ◽  
Genetic Characterization ◽  
Family Members ◽  
Binding Domain ◽  
Polymorphic Ventricular Tachycardia ◽  
Current Evidence ◽  
Incomplete Penetrance ◽  
Two Generations

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-related, bidirectional ventricular tachycardia and atrial tachyarrhythmia in the absence of either structural heart disease or prolonged QT interval. Autosomal dominant and recessive forms of CPVT because of mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin 2 (CASQ2) have been reported. The objective of this study was the clinical and genetic characterization of the family of an individual initially diagnosed as a child in 1978. Method: We collected family medical history and recorded a four-generation pedigree. We performed mutation analysis of RyR2 ``critical regions'' in the N-terminus, FKBP12.6 binding domain, Ca2+ binding domain, and transmembrane domains of the C-terminus by direct sequencing. Results: CPVT was diagnosed in two of the nine family members evaluated. Pedigree analysis suggested autosomal dominant disease transmission. There were no additional reports of seizures, pregnancy loss, neonatal death, or sudden cardiac death in family members. A novel RyR2 gene variant (W4645R) was found in four family members including two without symptoms. RyR2-W4645R segregates with disease in this family with incomplete penetrance. The W4645 residue is evolutionarily conserved in the transmembrane region adjacent to previously reported disease-causing mutations. Based on sorting intolerant from tolerant analysis of protein structure, RyR2-W4645R is predicted to be deleterious. Conclusions: All current evidence supports RyR2-W4645R as a disease-causing variant, which was silent in persons for two generations before causing symptoms in persons for the next two generations, beginning in 1978.

scholarly journals Detection of a new deleterious SGCE gene variant in Moroccan family with inherited Myoclonic-dystonia

2021 ◽  
Author(s):  
chbel faiza ◽  
charoute hicham ◽  
Boulouiz redouane ◽  
Hamdaoui Hasna ◽  
Mossafa Houssein ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Dominant Mode ◽  
Incomplete Penetrance ◽  
Gene Variant ◽  
Pathogenic Variants ◽  
Modeling Analysis ◽  
Moroccan Family ◽  
Myoclonus Dystonia ◽  
Maternal Imprinting ◽  
Mode Of Inheritance

Myoclonus-Dystonia is a neuropsychiatric disorder with autosomal dominant mode of inheritance with variable severity and incomplete penetrance. Pathogenic variants in SGCE are the most frequent genetic cause of M-D with maternal imprinting. Herein we report a new deleterious variant based on protein modeling analysis (c.662G> T) inherited in moroccan family.

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

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