Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

BackgroundGermline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers.MethodsA retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.ResultsTumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).ConclusionsOverall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

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WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2017.10.002 ◽

2018 ◽

Vol 102 (1) ◽

pp. 27-43 ◽

Cited By ~ 39

Author(s):

Janson J. White ◽

Juliana F. Mazzeu ◽

Zeynep Coban-Akdemir ◽

Yavuz Bayram ◽

Vahid Bahrambeigi ◽

...

Keyword(s):

Wnt Signaling ◽

Genetic Heterogeneity ◽

Robinow Syndrome

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Spondyloocular Syndrome: A Novel XYLT2 Variant with Description of the Neonatal Phenotype

Frontiers in Genetics ◽

10.3389/fgene.2021.761264 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gabriella Doddato ◽

Alessandra Fabbiani ◽

Chiara Fallerini ◽

Mirella Bruttini ◽

Theodora Hadjistilianou ◽

...

Keyword(s):

Autosomal Recessive ◽

Phenotypic Variability ◽

Autosomal Recessive Inheritance ◽

Nuchal Translucency ◽

Gene Encoding ◽

Nasal Bridge ◽

Facial Profile ◽

Pathogenic Variants ◽

Skeletal Defects ◽

Bone Abnormalities

Spondyloocular syndrome (SOS) is a skeletal disorder caused by pathogenic variants in XYLT2 gene encoding a xylotransferase involved in the biosynthesis of proteoglycans. This condition, with autosomal recessive inheritance, has a high phenotypic variability. It is characterized by bone abnormalities (osteoporosis, fractures), eye and cardiac defects, hearing impairment, and varying degrees of developmental delay. Until now only 20 mutated individuals have been reported worldwide. Here, we describe two siblings from consanguineous healthy parents in which a novel homozygous frameshift variant c.1586dup p(Thr530Hisfs*) in the XYLT2 gene was detected by exome sequencing (ES). The first patient (9 years) presented short stature with skeletal defects, long face, hearing loss and cataract. The second patient, evaluated at a few days of life, showed macrosomia, diffuse hypertrichosis on the back, overabundant skin in the retronucal area, flattened facial profile with drooping cheeks, elongated eyelid rims, wide and flattened nasal bridge and turned down corners of the mouth. During the prenatal period, high nuchal translucency and intestinal hyperechogenicity were observed at ultrasound. In conclusion, these two siblings with a novel pathogenic variant in XYLT2 further expand the clinical and mutational spectrum of SOS.

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High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature

Acta Endocrinologica ◽

10.1530/eje-19-0771 ◽

2020 ◽

Vol 182 (3) ◽

pp. 243-253

Author(s):

L Stavber ◽

T Hovnik ◽

P Kotnik ◽

L Lovrečić ◽

J Kovač ◽

...

Keyword(s):

Short Stature ◽

Phenotypic Variability ◽

Bone Age ◽

Growth Patterns ◽

Comparative Genomic ◽

Study Cohort ◽

Pathogenic Variants ◽

Intragenic Deletion ◽

Number Variation ◽

Personalized Approach

Context Defining the underlying etiology of idiopathic short stature (ISS) improves the overall management of an individual. Objective To assess the frequency of pathogenic ACAN variants in selected individuals. Design The single-center cohort study was conducted at a tertiary university children’s hospital. From 51 unrelated patients with ISS, the 16 probands aged between 3 and 18 years (12 females) with advanced bone age and/or autosomal dominant inheritance pattern of short stature were selected for the study. Fifteen family members of ACAN-positive probands were included. Exome sequencing was performed in all probands, and additional copy number variation (CNV) detection was applied in selected probands with a distinct ACAN-associated phenotype. Results Systematic phenotyping of the study cohort yielded 37.5% (6/16) ACAN-positive probands, with all novel pathogenic variants, including a 6.082 kb large intragenic deletion, detected by array comparative genomic hybridization (array CGH) and exome data analysis. All variants were co-segregated with short stature phenotype, except in one family member with the intragenic deletion who had an unexpected growth pattern within the normal range (−0.5 SDS). One patient presented with otosclerosis, a sign not previously associated with aggrecanopathy. Conclusions ACAN pathogenic variants presented a common cause of familial ISS. The selection criteria used in our study were suggested for a personalized approach to genetic testing of the ACAN gene in clinical practice. Our results expanded the number of pathogenic ACAN variants, including the first intragenic deletion, and suggested CNV evaluation in patients with typical clinical features of aggrecanopathy as reasonable. Intra-familial phenotypic variability in growth patterns should be considered.

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A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism

Hormone Research in Paediatrics ◽

10.1159/000495800 ◽

2019 ◽

Vol 92 (1) ◽

pp. 56-63

Author(s):

Naomi Hatabu ◽

Naho Katori ◽

Takeshi Sato ◽

Naonori Maeda ◽

Eri Suzuki ◽

...

Keyword(s):

Primary Hyperparathyroidism ◽

Phenotypic Variability ◽

Early Adulthood ◽

Familial Case ◽

Incomplete Penetrance ◽

Heterozygous Deletion ◽

Imaging Studies ◽

Intact Pth ◽

Pathogenic Variants ◽

Pth Level

Introduction: Primary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT. Case Description: A 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the “second hit.” Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history. Conclusions: These data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.

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Coinheritance of 2 New Potentially Damaging Heterozygous COL7A1 Variants in a Family With Autosomal Dominant Epidermolysis Bullosa Pruriginosa

Pediatric and Developmental Pathology ◽

10.1177/1093526618761497 ◽

2018 ◽

Vol 21 (6) ◽

pp. 580-584

Author(s):

Gordon I Hale ◽

Marta C Cohen ◽

Oliver W Quarrell ◽

John A McGrath ◽

Andrew G Messenger

Keyword(s):

Epidermolysis Bullosa ◽

Autosomal Dominant ◽

Late Onset ◽

Phenotypic Variability ◽

Incomplete Penetrance ◽

Histopathological Diagnosis ◽

Delayed Presentation ◽

Pathogenic Variants ◽

Type Vii Collagen ◽

Phenotypic And Genotypic Variability

Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of EB which is characterized by intense pruritus with blistering and nodular or lichenoid lesions most prominent on the lower extremities. It is caused by variants in COL7A1 which encodes for type VII collagen. There is wide phenotypic and genotypic variability between affected individuals. We report 2 potentially pathogenic variants in COL7A1 occurring on the same allele in a family with EBP and autosomal dominant inheritance. Late-onset EBP and incomplete penetrance may lead to delayed presentation in affected family members with the same variants. The broad phenotypic variability seen in EBP suggests that further genotypic and environmental factors may influence presentation. Genetic and histopathological diagnosis is essential, given the considerable overlap with clinically similar presentations such as hypertrophic lichen planus.

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Further evidence for POMK as candidate gene for WWS with meningoencephalocele

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01454-0 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Luisa Paul ◽

Katrin Rupprich ◽

Adela Della Marina ◽

Anja Stein ◽

Magdeldin Elgizouli ◽

...

Keyword(s):

Muscular Dystrophy ◽

Clinical Diagnosis ◽

Phenotypic Variability ◽

Congenital Muscular Dystrophy ◽

Monozygotic Twins ◽

Matrix Composition ◽

Cortical Malformation ◽

Pathogenic Variants ◽

And Function ◽

Cns Malformations

Abstract Background Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Bi-allelic pathogenic variants in POMK are the cause of a broad spectrum of alpha-dystroglycanopathies. POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition. Results Here, we report on male monozygotic twins with severe CNS malformations (hydrocephalus, cortical malformation, hypoplastic cerebellum, and most prominently occipital meningocele), eye malformations and highly elevated creatine kinase, indicating the clinical diagnosis of a congenital muscular dystrophy (alpha-dystroglycanopathy). Both twins were found to harbor a homozygous nonsense mutation c.640C>T, p.214* in POMK, confirming the clinical diagnosis and supporting the concept that POMK mutations can be causative of WWS. Conclusion Our combined data suggest a more important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families; only five showed the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. We expand the phenotypic and mutational spectrum of POMK-associated WWS and provide evidence of the broad phenotypic variability of POMK-associated disease.

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The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?

International Journal of Molecular Sciences ◽

10.3390/ijms21176434 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6434

Author(s):

Maria Bueno Marinas ◽

Rudy Celeghin ◽

Marco Cason ◽

Gaetano Thiene ◽

Cristina Basso ◽

...

Keyword(s):

Gene Expression Regulation ◽

Phenotypic Variability ◽

Incomplete Penetrance ◽

Primary Role ◽

Arrhythmogenic Cardiomyopathy ◽

Small Noncoding Rnas ◽

Early Disease Detection ◽

Pathogenic Variants ◽

Fatty Replacement ◽

Genes Encoding

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease characterized by a progressive fibro-fatty replacement of the working myocardium and by life-threatening arrhythmias and risk of sudden cardiac death. Pathogenic variants are identified in nearly 50% of affected patients mostly in genes encoding for desmosomal proteins. AC incomplete penetrance and phenotypic variability advocate that other factors than genetics may modulate the disease, such as microRNAs (miRNAs). MiRNAs are small noncoding RNAs with a primary role in gene expression regulation and network of cellular processes. The implication of miRNAs in AC pathogenesis and their role as biomarkers for early disease detection or differential diagnosis has been the objective of multiple studies employing diverse designs and methodologies to detect miRNAs and measure their expression levels. Here we summarize experiments, evidence, and flaws of the different studies and hitherto knowledge of the implication of miRNAs in AC pathogenesis and diagnosis.

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New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly

Molecular Syndromology ◽

10.1159/000515044 ◽

2021 ◽

pp. 1-15

Author(s):

Viviane Freitas de Castro ◽

Daniel Mattos ◽

Flavia Martinez de Carvalho ◽

Denise Pontes Cavalcanti ◽

Milagros M. Duenas-Roque ◽

...

Keyword(s):

Latin American ◽

Sanger Sequencing ◽

Phenotypic Variability ◽

Phenotypic Expression ◽

Driver Gene ◽

Incomplete Penetrance ◽

Phenotype Correlation ◽

Pathogenic Variants ◽

Facial Defects ◽

Domain Conservation

Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the SHH, SIX3, ZIC2, and TGIF1 genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new SHH variants and a third known SIX3 likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with SHH pathogenic variants, presented benign variants of the SHH, SIX3, ZIC2, and TGIF1 genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same SIX3 variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.

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Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Genes ◽

10.3390/genes12101508 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1508

Author(s):

Isabelle Jéru ◽

Amira Nabil ◽

Gehad El-Makkawy ◽

Olivier Lascols ◽

Corinne Vigouroux ◽

...

Keyword(s):

Phenotypic Variability ◽

Genetic Disorders ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Compound Heterozygous ◽

Partial Lipodystrophy ◽

Mandibular Hypoplasia ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Mandibuloacral Dysplasia

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations.

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