Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy

2021 ◽  
Author(s):  
Laura Mary ◽  
Elsa Nourisson ◽  
Claire Feger ◽  
Vincent Laugel ◽  
Denys Chaigne ◽  
...  
Keyword(s):  
Intellectual Deficiency ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum

scholarly journals Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature

2019 ◽  
Vol 09 (02) ◽  
pp. 117-120
Author(s):  
Pavalan Selvam ◽  
Shekhar Singh ◽  
Angita Jain ◽  
Herjot Atwal ◽  
Paldeep S. Atwal
Keyword(s):  
Sequence Analysis ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Review Of The Literature ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
The Family ◽  
Type Xi Collagen ◽  
Exome Sequence

AbstractOtospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

scholarly journals The First Description of Monozygotic Twin Females Discordant for the Craniofrontonasal Syndrome Phenotype and the Report of Four Novel Pathogenic Variants in the EFNB1 Gene

2021 ◽  
Author(s):  
Ewelina Bukowska-Olech ◽  
Paweł Gawliński ◽  
Anna Jakubiuk-Tomaszuk ◽  
Maria Jędrzejowska ◽  
Ewa Obersztyn ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Clinical Phenotype ◽  
Monozygotic Twins ◽  
Monozygotic Twin ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Targeted Ngs ◽  
Primary Finding ◽  
Unusual Phenomenon ◽  
Craniofacial Features

Abstract Background: Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder that results from pathogenic variants in the EFNB1 gene. The syndrome paradoxically presents with greater severity of the symptoms in heterozygous females than hemizygous males.Results: Our primary finding was the description of monozygotic twins, i.e., patients 5 & 6, discordant for the CFNS phenotype. Intriguingly, patient 5 presented classical CFNS gestalt, whereas patient 6 manifested only very subtle craniofacial features, not resembling CFNS. Besides, we have expanded the mutational spectrum of the EFNB1 gene through reporting four novel pathogenic variants – p.(Trp12*), p.(Cys64Phe), p.(Tyr73Metfs*86), p.(Glu210*). All those alterations were found applying either targeted NGS of a custom gene panel or PCR followed by Sanger sequencing and evaluated using in silico predictors. Lastly, we have also expanded the CFNS phenotypic spectrum by describing in patient 3 novel features of the syndrome, such as bifid hallux, bicornuate uterus, and abnormal right ovary segmented into six parts Conclusions: We have described the unreported so far differences of the clinical phenotype in the monozygotic twin patients 5 & 6 harbouring an identical p.(Glu210*) variant located in the EFNB1 gene. With our finding, we have pointed to an unusual phenomenon of mildly affected females with CFNS, who may not manifest features suggestive of the syndrome. Consequently, this study may be valuable for geneticists consulting patients with craniofacial disorders.

scholarly journals Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

2021 ◽  
Vol 12 ◽  
Author(s):  
Gianluca Piccolo ◽  
Giuseppe d'Annunzio ◽  
Elisabetta Amadori ◽  
Antonella Riva ◽  
Paola Borgia ◽  
...  
Keyword(s):  
Genetic Basis ◽  
First Year ◽  
Arthrogryposis Multiplex Congenita ◽  
Neurodevelopmental Delay ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Distal Muscle ◽  
Neurodevelopmental Impairment ◽  
First Year Of Life

Wieacker-Wolff syndrome (WWS) is an X-linked Arthrogryposis Multiplex Congenita (AMC) disorder associated with broad neurodevelopmental impairment. The genetic basis of WWS lies in hemizygous pathogenic variants in ZC4H2, encoding a C4H2 type zinc-finger nuclear factor abundantly expressed in the developing human brain. The main clinical features described in WWS families carrying ZC4H2 pathogenic variants encompass having a short stature, microcephaly, birth respiratory distress, arthrogryposis, hypotonia, distal muscle weakness, and broad neurodevelopmental delay. We hereby report a Sicilian family with a boy clinically diagnosed with WWS and genetically investigated with exome sequencing (ES), leading to the identification of a c.593G>A (p. R198Q) hemizygous pathogenic variant in the ZC4H2 gene. During the first year of life, the onset of central hypoadrenalism led to recurrent hypoglycemic events, which likely contributed to seizure susceptibility. Also, muscle biopsy studies confirmed a pathology of the muscle tissue and revealed peculiar abnormalities of the neuromuscular junction. In conclusion, we expand the phenotypic spectrum of the WWS-related neurodevelopmental disorders and discuss the role of ZC4H2 in the context of the potential neuroendocrinological and neuromuscular features associated with this condition.

scholarly journals Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes

2019 ◽  
Vol 62 (12) ◽  
pp. 103588 ◽  
Author(s):  
Elizabeth J. Bhoj ◽  
Damien Haye ◽  
Annick Toutain ◽  
Dominique Bonneau ◽  
Irene Kibæk Nielsen ◽  
...  
Keyword(s):  
Critical Review ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum

scholarly journals Expansion of phenotypic spectrum of MYO15A pathogenic variants to include postlingual onset of progressive partial deafness

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Mun Young Chang ◽  
Chung Lee ◽  
Jin Hee Han ◽  
Min Young Kim ◽  
Hye-Rim Park ◽  
...  
Keyword(s):  
Pathogenic Variants ◽  
Phenotypic Spectrum

Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1): Are We Diagnosing Yet?

2021 ◽  
Author(s):  
Chaithanya Reddy ◽  
Pradip Paria ◽  
Debajyoti Chatterjee ◽  
Arushi G. Saini ◽  
Renu Suthar ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Spinal Muscular Atrophy ◽  
Selection Criteria ◽  
Muscular Atrophy ◽  
Binding Protein ◽  
Interesting Case ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum

AbstractThe spectrum of disorders associated with the IGHMBP2 (immunoglobulin μ-binding protein 2) gene pathogenic variants is still unknown. We discuss here an interesting case of genetically confirmed spinal muscular atrophy with respiratory distress type 1 (SMARD1) with atypical sparing of the diaphragm, thus expanding the phenotypic spectrum of this intriguing disorder and also highlight the importance of reconsidering the selection criteria for considering IGHMBP2 pathogenic variants.

scholarly journals Retinopathy and optic atrophy: Expanding the phenotypic spectrum of pathogenic variants in the AARS2 gene

2017 ◽  
Vol 39 (1) ◽  
pp. 99-102 ◽  
Author(s):  
Jason H. Peragallo ◽  
Stephanie Keller ◽  
Marjo S. van der Knaap ◽  
Bruno P. Soares ◽  
Suma P. Shankar
Keyword(s):  
Optic Atrophy ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum

scholarly journals Clinical and molecular characterization of craniofrontonasal syndrome: new symptoms and novel pathogenic variants in the EFNB1 gene

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ewelina Bukowska-Olech ◽  
Paweł Gawliński ◽  
Anna Jakubiuk-Tomaszuk ◽  
Maria Jędrzejowska ◽  
Ewa Obersztyn ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Monozygotic Twins ◽  
Monozygotic Twin ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Targeted Ngs ◽  
Primary Finding ◽  
Unusual Phenomenon ◽  
Craniofacial Features

Abstract Background Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder that results from pathogenic variants in the EFNB1 gene. The syndrome paradoxically presents with greater severity of the symptoms in heterozygous females than hemizygous males. Results We have recruited and screened a female cohort affected with CFNS. Our primary finding was the description of monozygotic twins, i.e., patients 5 and 6, discordant for the CFNS phenotype. Intriguingly, patient 5 presented classical CFNS gestalt, whereas patient 6 manifested only very subtle craniofacial features, not resembling CFNS. Besides, we have expanded the mutational spectrum of the EFNB1 gene through reporting four novel pathogenic variants—p.(Trp12*), p.(Cys64Phe), p.(Tyr73Metfs*86), p.(Glu210*). All those alterations were found applying either targeted NGS of a custom gene panel or PCR followed by Sanger sequencing and evaluated using in silico predictors. Lastly, we have also expanded the CFNS phenotypic spectrum by describing in patient 3 several novel features of the syndrome, such as bifid hallux, bicornuate uterus, and abnormal right ovary segmented into six parts. Conclusions We have described the unreported so far differences of the clinical phenotype in the monozygotic twin patients 5 and 6 harboring an identical p.(Glu210*) variant located in the EFNB1 gene. With our finding, we have pointed to an unusual phenomenon of mildly affected females with CFNS, who may not manifest features suggestive of the syndrome. Consequently, this study may be valuable for geneticists consulting patients with craniofacial disorders.

scholarly journals Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Riccardo Sangermano ◽  
Iris Deitch ◽  
Virginie G. Peter ◽  
Rola Ba-Abbad ◽  
Emily M. Place ◽  
...  
Keyword(s):  
Early Onset ◽  
Rare Variants ◽  
Joubert Syndrome ◽  
Phenotypic Correlation ◽  
Genetic Modifiers ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Spectrum Detection ◽  
Sequencing Studies ◽  
Sporadic Cases

AbstractPathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype–phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.

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