Visual Function and Ophthalmological Findings in CHARGE Syndrome: Revision of Literature, Definition of a New Clinical Spectrum and Genotype Phenotype Correlation

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype–ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype–phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do.

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Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

10.1101/2021.11.07.467657 ◽

2021 ◽

Author(s):

Rie Asada Kitamura ◽

Kristina Maxwell ◽

Wenjuan Ye ◽

Kelly Kries ◽

Cris Brown ◽

...

Keyword(s):

Stem Cell ◽

Correlation Analysis ◽

Combination Treatment ◽

Disease Model ◽

Wolfram Syndrome ◽

Phenotype Correlation ◽

Chemical Chaperones ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation ◽

Therapeutic Development

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.

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Genotype-phenotype correlation in fibrous dysplasia/McCune-Albright syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab053 ◽

2021 ◽

Author(s):

Maria Zhadina ◽

Kelly L Roszko ◽

Raya E S Geels ◽

Luis F de Castro ◽

Michael T Collins ◽

...

Keyword(s):

Fibrous Dysplasia ◽

Phenotype Correlation ◽

Cross Sectional ◽

Mccune Albright Syndrome ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation ◽

Large Patient ◽

Pancreatic Involvement ◽

Albright Syndrome ◽

Mccune Albright

Abstract Context Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood. Objective 1) To determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort. Design Retrospective cross-sectional analysis Main Outcome Measures Correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data. Results Sixty-one subjects were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two subjects (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the two groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a non-significant association of cancer with the R201H variant. Conclusion There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for future development of targeted therapies.

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Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL)

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa084 ◽

2020 ◽

Vol 4 (8) ◽

Author(s):

Daniel R Tilden ◽

Jonathan H Sheehan ◽

John H Newman ◽

Jens Meiler ◽

John A Capra ◽

...

Keyword(s):

Medical Records ◽

Rare Variants ◽

Serum Alkaline Phosphatase ◽

Clinical Care ◽

Test Results ◽

Phenotype Correlation ◽

Clinical Phenotypes ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation ◽

Genetic Test Results

Abstract Context Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity as well as musculoskeletal and/or dental disease. While the majority of subjects with HPP carry a pathogenic variant in the ALPL gene or its regulatory regions, individual pathogenic variants are often not tightly correlated with clinical symptomatology. We sought to better understand the genotype/phenotype correlation in HPP by examining the clinical and biochemical data of 37 subjects with 2 rare variants in ALPL. Methods Through BioVU, a DNA biobank that pairs individuals’ genetic information with their de-identified medical records, we identified subjects with 2 rare variants with distinct reported clinical phenotypes (p.D294A and p.T273M). We then performed a manual review of these subjects’ de-identified medical records along with computational modeling of protein structure to construct a genetic, biochemical and clinical phenotype for each subject and variant. Results Twenty subjects with the p.D294A variant and 17 with the p.T273M variant had sufficient data for analysis. Among subjects in our cohort with the p.D294A variant, 6 (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while 4 subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants. Conclusions Given the loose genotype/phenotype correlation in HPP seen in our cohort, clinical context is crucial for the interpretation of genetic test results to guide clinical care in this population. Otherwise, over- or under-diagnosis may occur, resulting in misidentification of those who may benefit from additional screening and perhaps pharmacologic intervention.

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Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0234 ◽

2020 ◽

Vol 33 (1) ◽

pp. 79-88 ◽

Cited By ~ 2

Author(s):

Anil Kumar ◽

Vandana Jain ◽

Madhumita Roy Chowdhury ◽

Manoj Kumar ◽

Punit Kaur ◽

...

Keyword(s):

Growth Factor ◽

Short Stature ◽

Serum Insulin ◽

Significant Proportion ◽

Idiopathic Short Stature ◽

Insulin Like Growth Factor ◽

Phenotype Correlation ◽

Indian Children ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation

AbstractBackgroundOur objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation.MethodsWe recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <−1 standard deviation. The genotype-phenotype correlation was studied.ResultsFour children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as ‘disease causing’, and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop.ConclusionsPathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.

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Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation

The American Journal of Human Genetics ◽

10.1086/500273 ◽

2006 ◽

Vol 78 (2) ◽

pp. 303-314 ◽

Cited By ~ 255

Author(s):

Seema R. Lalani ◽

Arsalan M. Safiullah ◽

Susan D. Fernbach ◽

Karine G. Harutyunyan ◽

Christina Thaller ◽

...

Keyword(s):

Charge Syndrome ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation

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Genotype–phenotype correlation in patients with Usher syndrome and pathogenic variants in MYO7A : implications for future clinical trials

Acta Ophthalmologica ◽

10.1111/aos.14795 ◽

2021 ◽

Author(s):

Lilián Galbis‐Martínez ◽

Fiona Blanco‐Kelly ◽

Gema García‐García ◽

Almudena Ávila‐Fernández ◽

Teresa Jaijo ◽

...

Keyword(s):

Clinical Trials ◽

Usher Syndrome ◽

Phenotype Correlation ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation

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Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation

Genes ◽

10.3390/genes12091360 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1360

Author(s):

Carolina Sanchez-Jimeno ◽

Fiona Blanco-Kelly ◽

Fermina López-Grondona ◽

Rebeca Losada-Del Pozo ◽

Beatriz Moreno ◽

...

Keyword(s):

Intellectual Disability ◽

Attention Deficit ◽

Autism Spectrum ◽

Global Developmental Delay ◽

Sequence Variants ◽

Loss Of Function ◽

Phenotype Correlation ◽

Feeding Difficulties ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3′ end of the gene, confirming the genotype-phenotype correlation initially described.

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Evidence for a Genotype–Phenotype Correlation in Patients with Pathogenic GLUT2 (SLC2A2) Variants

Genes ◽

10.3390/genes12111785 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1785

Author(s):

Sarah C. Grünert ◽

Anke Schumann ◽

Federico Baronio ◽

Konstantinos Tsiakas ◽

Simona Murko ◽

...

Keyword(s):

Residual Activity ◽

Glycogen Storage ◽

Hepatic Glycogen ◽

Tubular Dysfunction ◽

Renal Tubular Dysfunction ◽

Phenotype Correlation ◽

Membrane Expression ◽

Pathogenic Variants ◽

Functional Variants ◽

Genotype Phenotype Correlation

Fanconi-Bickel syndrome (FBS) is a very rare but distinct clinical entity with the combined features of hepatic glycogen storage disease, generalized proximal renal tubular dysfunction with disproportionately severe glucosuria, and impaired galactose tolerance. Here, we report five cases (out of 93 diagnosed in our lab) with pathogenic variants on both GLUT2 (SLC2A2) alleles. They come from 3 families and presented with an exceptionally mild clinical course. This course was correlated to data from old and most recent expression and transport studies in Xenopus oocytes. GLUT2 genotype in patients 1 and 2 was p.[153_4delLI];[P417R] with the first variant exhibiting normal membrane expression and partially retained transport activity (5.8%) for 2-deoxyglucose. In patient 3, the very first GLUT2 variant ever detected (p.V197I) was found, but for the first time it was present in a patient in the homozygous state. This variant had also shown unaffected membrane expression and remarkable residual activity (8%). The genotype in patient 4, p.[153_4delLI];[(E440A)], again included the 2-amino-acid deletion with residual transporter function, and patient 5 is the first found to be homozygous for this variant. Our results provide further evidence for a genotype-phenotype correlation in patients with GLUT2 variants; non-functional variants result in the full picture of FBS while dysfunctional variants may result in milder presentations, even glucosuria only, without other typical signs of FBS.

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Congenital Central Hypoventilation Syndrome in Neonates: Report of Fourteen New Cases and A Review of the Literature

10.21203/rs.3.rs-18814/v1 ◽

2020 ◽

Author(s):

Mei Mei ◽

Lin Yang ◽

Yulan Lu ◽

Laishuan Wang ◽

Guoqiang Cheng ◽

...

Keyword(s):

Current Knowledge ◽

Molecular Testing ◽

Congenital Central Hypoventilation Syndrome ◽

Phenotype Correlation ◽

Mild Phenotype ◽

Pathogenic Variants ◽

Neonatal Onset ◽

Genotype Phenotype Correlation ◽

Central Hypoventilation ◽

Hypoventilation Syndrome

Abstract Background: Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disorder caused by pathogenic variants in PHOX2B gene. Characteristics of neonatal-onset CCHS cases have not been well assessed. Our study aimed to expand current knowledge of clinical and genetic features of neonates with CCHS and provide data on the genotype-phenotype correlation.Methods: We made a retrospective analysis of 14 neonates carrying PHOX2B pathogenic variants from 2014 to 2019 and we reviewed previously published neonatal-onset cases. Clinical and genetic data were analyzed. Moreover, genotype-phenotype correlation analysis was performed.Results: We identified a total of 60 cases with neonatal-onset CCHS including 14 novel cases from our local cohort. Nearly 20% (18.2%, 10/55) of the patients were born prematurely. Nearly half (46.2%, 18/39) of the patients had abnormal family history. Polyhydramnios was observed in 21.3% (10/47) of the patients. About 90% of the patients manifested hypoventilation in the first week. Forty-six (76.7%) patients were classified as severer-CCHS. Gastrointestinal manifestations were observed in 71.7% of the patients. Approximately twofold more males than females were affected by Hirschprung disease (HSCR)/variant HSCR (75.8% vs 35%, P=0.003). Neural crest tumor occurred in 9.1% (4/44) patients. Half patients had PARMs in PHOX2B and the left had 23 distinct non-PARMs (NPARMs) with one novel variant (c.684dup). The prevalence of HSCR and mild-CCHS among patients with NPARMs was significantly greater than that of the patients with PARMs.Conclusions: This report provides a large cohort of neonatal-onset CCHS cases. The results indicate that severe hypoventilation and HSCR are frequently observed in this group. NPARMs accounted for half of the cohort with some genotypes tend to be associated with mild phenotype. Molecular testing in suspicious neonates and genetic counseling for CCHS families are highly recommended.

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

Sexual Development ◽

10.1159/000509812 ◽

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 SRD5A2 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 SRD5A2, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in SRD5A2, 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 SRD5A2 and in nearly 90% of those without pathogenic variants in SRD5A2 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 SRD5A2 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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