scholarly journals Further Expansion of the Mutational Spectrum of 3MC Syndrome: A Novel MASP1 Pathogenic Variant in a Male Patient

2021 ◽  
pp. 1-7
Author(s):  
Nihat Bugra Agaoglu ◽  
Ozlem Akgun Dogan
Keyword(s):  
Male Patient ◽  
Cleft Lip ◽  
Postnatal Growth ◽  
Pathogenic Variant ◽  
Facial Dysmorphism ◽  
Compound Heterozygous ◽  
Aortic Dilatation ◽  
Pathogenic Variants ◽  
Growth Deficiency ◽  
Cleft Lip Palate

The 3MC syndrome is a rare autosomal recessive syndrome characterized by facial dysmorphism, multiple congenital abnormalities, and postnatal growth deficiency. Hypertelorism, blepharophimosis, blepharoptosis, high-arched eyebrows, and cleft lip/palate compose the facial gestalt, which is the key component for diagnosing the syndrome. Biallelic pathogenic variants in <i>MASP1, COLEC11</i>, and <i>COLEC10</i> are responsible for 3MC syndrome in which both genotypic and phenotypic heterogeneity is described. To date, 16 homozygous/compound heterozygous pathogenic variations in 27 patients from 22 families have been reported in the <i>MASP1</i> gene associated with 3MC syndrome. Here, we report a male patient with a novel homozygous pathogenic variant in <i>MASP1</i> in whom macrocephaly, pyloric stenosis, and prenatal findings including polyhydramnios, aortic dilatation, and intracranial cysts beside the distinctive facial features were detected. Reporting detailed clinical and molecular findings in patients is pivotal in terms of enabling the phenotypic and genotypic spectrum of this rare syndrome to be delineated.

scholarly journals Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development

2019 ◽  
Author(s):  
Marshall Lukacs ◽  
Tia Roberts ◽  
Praneet Chatuverdi ◽  
Rolf W. Stottmann
Keyword(s):  
Neural Crest ◽  
Neural Development ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Folate Receptor ◽  
Neural Crest Cell ◽  
Specific Expression ◽  
Hypomorphic Mutation ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

AbstractThe glycosylphosphatidylinositol (GPI) anchor attaches nearly 150 proteins to the cell surface. Patients with pathogenic variants in GPI biosynthetic pathway genes display an array of phenotypes including seizures, developmental delay, dysmorphic facial features and cleft palate. There is virtually no mechanism to explain these phenotypes. we identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypomorphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2). Pgap2 is one of the final proteins in the GPI biosynthesis pathway and is required for anchor maturation. We found the Clpex mutation results in a global decrease in surface GPI expression. Surprisingly, Pgap2 showed tissue specific expression with enrichment in the affected tissues of the Clpex mutant. We found the phenotype in Clpex mutants is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium, as is observed in the GPI anchored Folate Receptor 1-/- mouse. We showed folinic acid supplementation in utero can rescue the cleft lip phenotype in Clpex. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency in the Wnt1-Cre lineage. These mutants developed median cleft lip and palate demonstrating a cell autonomous role for GPI biosynthesis in NCC development.

scholarly journals Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Niu Li ◽  
Yufei Xu ◽  
Yi Zhang ◽  
Guoqiang Li ◽  
Tingting Yu ◽  
...  
Keyword(s):  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Multiple Systems ◽  
Feeding Difficulties ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

scholarly journals CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 391
Author(s):  
Arthavan Selvanathan ◽  
Cheng Yee Nixon ◽  
Ying Zhu ◽  
Luigi Scietti ◽  
Federico Forneris ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cleft Lip ◽  
Structural Characteristics ◽  
Molecular Data ◽  
Diffuse Gastric Cancer ◽  
Pathogenic Variants ◽  
Orofacial Clefting ◽  
Cleft Lip Palate ◽  
Cdh1 Mutation ◽  
Mutation Distribution

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.

Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

2022 ◽  
pp. 1-8
Author(s):  
Liliana Fernández Hernández ◽  
Miguel A. Alcántara Ortigoza ◽  
Sandra E. Ramos Angeles ◽  
Ariadna González-del Angel
Keyword(s):  
Intellectual Disability ◽  
Sanger Sequencing ◽  
Cleft Lip ◽  
De Novo ◽  
Deletion Syndrome ◽  
Facial Dysmorphism ◽  
Brain Malformations ◽  
Bilateral Cleft Lip ◽  
Cleft Lip Palate ◽  
Distinctive Phenotype

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the <i>MEF2C</i> gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype. To date, nearly 40 cases have been reported; the deletion size and clinical spectrum are variable, and at least 6 cases without <i>MEF2C</i> involvement have been documented. We herein report the clinical and cytogenomic findings of an 11-year-old girl who has a 5q14.3q21.1 de novo deletion that does not involve <i>MEF2C</i> but shares the clinical features described in other reported patients. Moreover, she additionally presents with bilateral cleft-lip palate (CLP), which has not been previously reported as a feature of the syndrome. The most frequent syndromic forms of CLP were ruled out in our patient mainly by clinical examination, and Sanger sequencing was performed to discard the presence of a <i>TBX22</i> gene (MIM*300307) defect. Our report suggests CLP as a possible unreported feature and redefines the critical phenotypic regions of 5q14.3 deletion syndrome.

Cleft Lip and Palate in Ectodermal Dysplasia

2020 ◽  
pp. 105566562094912
Author(s):  
Ingrid M. Ganske ◽  
Tim Irwin ◽  
Olivia Langa ◽  
Joseph Upton ◽  
Wen-Hann Tan ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Ectodermal Dysplasia ◽  
Phenotypic Expression ◽  
Velopharyngeal Insufficiency ◽  
Pathogenic Variants ◽  
Orofacial Clefting ◽  
Outcomes Measures ◽  
Cleft Lip Palate ◽  
Dentofacial Orthopedics

Objective: Ectodermal dysplasia (ED) comprises multiple syndromes that affect skin, hair, nails, and teeth, and sometimes are associated with orofacial clefting. The purpose of this study is to (1) identify the prevalence and characteristics of cleft lip and/or palate (CL/P) in patients with ED and (2) describe the management and outcomes. Design: Retrospective review from 1990 to 2019. Patients: All patients with ED treated at Boston Children's Hospital. Main Outcomes Measures: Prevalence of CL/P was calculated and clinical details recorded: phenotypic anomalies, cleft type, operative treatment, and results of repair. Results: Of 170 patients with a purported diagnosis of ED, 24 (14%) had CL/P. Anatomic categories were bilateral CL/P (67%), unilateral CL/P (8%), and cleft palate only (25%). The most common ED syndrome (37%) was ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC). Pathogenic variants in TP63 were the most frequent finding in the 11 patients who had genetic testing. Aberrations from a typical clinical course included failure of presurgical dentofacial orthopedics, dehiscence of nasolabial adhesion, and total palatal absence requiring free-flap construction. Two patients had prolonged postoperative admission for respiratory infection. High fistula (8%) and velopharyngeal insufficiency (33%) rates reflected the predominance of bilateral complete forms. Conclusions: As in other types of syndromic CL/P, cleft phenotypic expression in ED is more severe than the general cleft population. Further studies are needed to correlate genotype and phenotype for the distinct syndromes included in the ED spectrum.

Dental Evaluation of Kabuki Syndrome Patients

2009 ◽  
Vol 46 (6) ◽  
pp. 668-673 ◽  
Author(s):  
Camila Santos Teixeira ◽  
Claudia Renata Leite Silva ◽  
Rachel Sayuri Honjo ◽  
Débora Romeo Bertola ◽  
Lílian Maria José Albano ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Primary Teeth ◽  
Genetic Disorder ◽  
Mixed Dentition ◽  
Unknown Etiology ◽  
Kabuki Syndrome ◽  
Missing Teeth ◽  
Mild Phenotype ◽  
Growth Deficiency ◽  
Cleft Lip Palate

Kabuki syndrome is a genetic disorder of unknown etiology characterized by mental retardation, growth deficiency, and peculiar face (i.e., long palpebral fissures, eversion of the lateral third of the lower eyelids, prominent ears, and broad and depressed nasal tip). Oral manifestations commonly observed in Kabuki syndrome may comprise cleft lip/palate, bifid tongue and uvula, malocclusion, and dental abnormalities. We evaluated the dental findings of eight patients with Kabuki syndrome. One presented cleft palate; three presented caries; and seven had missing teeth, with the upper lateral incisors and inferior central incisors being the most commonly absent. All missing teeth were permanent, and there was no alteration of dental chronology or morphology. Because most patients had mixed dentition, the presence or absence of primary teeth was assessed through the parents’ reports. One patient presented an absent upper canine, which had not been reported previously in the literature. Dental findings may be helpful for clinical diagnosis, or they may be an additional finding to substantiate the diagnosis of Kabuki syndrome in children with mild phenotype.

scholarly journals Different Phenotypes in Pseudodominant Inherited Retinal Dystrophies

2021 ◽  
Vol 9 ◽  
Author(s):  
Imen Habibi ◽  
Yosra Falfoul ◽  
Hoai Viet Tran ◽  
Khaled El Matri ◽  
Ahmed Chebil ◽  
...  
Keyword(s):  
Index Patient ◽  
Pathogenic Variant ◽  
Compound Heterozygous ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Subretinal Fibrosis ◽  
Precise Diagnosis ◽  
Compound Heterozygous Variants ◽  
Successive Generations

Retinal dystrophies (RD) are a group of Mendelian disorders caused by rare genetic variations leading to blindness. A pathogenic variant may manifest in both dominant or recessive mode and clinical and genetic heterogeneity makes it difficult to establish a precise diagnosis. In this study, families with autosomal dominant RD in successive generations were identified, and we aimed to determine the disease's molecular origin in these consanguineous families. Whole exome sequencing was performed in the index patient of each family. The aim was to determine whether these cases truly represented examples of dominantly inherited RD, or whether another mode of inheritance might be applicable. Six potentially pathogenic variants in four genes were identified in four families. In index patient with enhanced S-cone syndrome in F1, we identified a new digenetic combination: a heterozygous variant p.[G51A];[=] in RHO and a homozygous pathogenic variant p.[R311Q];[R311Q] in NR2E3. Helicoid subretinal fibrosis associated with recessive NR2E3 variant p.[R311Q];[R311Q] was identified in F2. A new frameshift variant c.[105delG];[105delG] in RDH12 was found in F3 with cone-rod dystrophy. In F4, the compound heterozygous variants p.[R964*];[W758*] were observed in IMPG2 with a retinitis pigmentosa (RP) phenotype. We showed that both affected parents and the offspring, were homozygous for the same variants in all four families. Our results provide evidence that in consanguineous families, autosomal recessive can be transmitted as pseudodominant inheritance in RD patients, and further extend our knowledge of pathogenic variants in RD genes.

scholarly journals Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

2021 ◽  
Author(s):  
Waheed Awotoye ◽  
Peter A. Mossey ◽  
Jacqueline B. Hetmanski ◽  
Lord Jephthah Joojo Gowans ◽  
Mekonen A. Eshete ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cleft Lip ◽  
De Novo ◽  
Association Studies ◽  
Whole Genome ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

Abstract The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

scholarly journals Ocular Manifestations of the NAA10-Related Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Angela S. Gupta ◽  
Hind Al Saif ◽  
Jennifer M. Lent ◽  
Natario L. Couser
Keyword(s):  
Growth Failure ◽  
Postnatal Growth ◽  
Pathogenic Variant ◽  
Massively Parallel ◽  
Chromosome X ◽  
Dysmorphic Features ◽  
Ocular Manifestations ◽  
Pathogenic Variants ◽  
Postnatal Growth Failure ◽  
Myopic Astigmatism

The NAA10-related syndrome is a rare X-linked neurodevelopmental condition that was first described in 2011. The disorder is caused by pathogenic variants in the NAA10 gene located on chromosome X at position Xq28. Clinical features typically include severe psychomotor developmental delay, cardiac disease, dysmorphic features, postnatal growth failure, and hypotonia, although there is significant variability in the severity of the phenotype among affected individuals. We describe a 5-year-old female with the syndrome; massively parallel exome sequencing and analysis revealed the c.247C>T (p.Arg83Cys) pathogenic variant that has been previously reported in ten affected individuals. Ocular manifestations of the NAA10-related syndrome are not uncommon, although they have not been well characterized in literature reports. From a systematic review of previously published cases to date, ocular abnormalities are present in more than half of patients with the syndrome. Common ocular findings reported include astigmatism, hyperopia, cortical vision impairment, microphthalmia/anophthalmia, and hypertelorism. Our patient presented with growth restriction, dysmorphic features, and hypotonia. Ocular manifestations identified in this child include downslanting palpebral fissures, myopic astigmatism, nystagmus, and exotropia. We speculate that the type and severity of ocular defects present in individuals with the NAA10-related syndrome are dependent on the specific NAA10 pathogenic variant involved.

Spectrum of Pathogenic Variants in SRD5A2 in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency

2019 ◽  
Vol 13 (5-6) ◽  
pp. 228-239
Author(s):  
Anil Kumar ◽  
Rajni Sharma ◽  
Mohammed Faruq ◽  
Varun Suroliya ◽  
Manoj Kumar ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Wide Spectrum ◽  
Disorders Of Sex Development ◽  
Pathogenic Variant ◽  
Compound Heterozygous ◽  
Phenotype Correlation ◽  
Indian Children ◽  
Sex Development ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation

The aim of this study was to assess the prevalence of pathogenic variants in the <i>SRD5A2</i> gene in children with 46,XY disorders of sex development (DSD) with normal to high serum testosterone levels and absence of Müllerian structures on imaging and to evaluate the genotype-phenotype correlation. Seventy-five patients with 46,XY DSD and probable clinical diagnosis of 5α-reductase 2 deficiency or androgen insensitivity syndrome were enrolled. Genetic analysis was done for pathogenic variants in <i>SRD5A2</i>, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in <i>SRD5A2, </i>either homozygous or compound heterozygous, were identified in 25 of 75 (33.3%) patients. The hCG stimulated testosterone: dihydrotestosterone (T:DHT) ratio was elevated in all patients with pathogenic variants in <i>SRD5A2</i> and in nearly 90% of those without pathogenic variants in <i>SRD5A2</i> in whom this was assessed. The missense pathogenic variant p.R246Q was a hotspot. One novel pathogenic variant p.Y178*, and a variant p.F194I, not previously reported in patients with 5α-reductase 2 deficiency, were identified. The missense variant p.F194I was predicted as deleterious and damaging by in silico analysis and as likely to reduce the enzyme activity by protein modeling. In conclusion, pathogenic variants in <i>SRD5A2 </i>can be detected in a wide spectrum of Indian patients with 46,XY DSD. Molecular genetic analysis should be considered as a first-line test as the T:DHT ratio lacks specificity and a hotspot variant is present in a vast majority.

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