A Novel Heterozygous Variant in Exon 19 of NOTCH3 in a Saudi Family with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. The discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease.

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Multicentric Carpotarsal Osteolysis Syndrome in a Mother and Daughter with a MAFB Missense Variant and Natural History of the Disease

Molecular Syndromology ◽

10.1159/000517348 ◽

2021 ◽

pp. 1-6

Author(s):

Kelin Chen ◽

Malú Zamariolli ◽

Maria de Fátima de Faria Soares ◽

Vera Ayres Meloni ◽

Maria Isabel Melaragno

Keyword(s):

Natural History ◽

Autosomal Dominant ◽

Clinical Manifestations ◽

Missense Variant ◽

Heterozygous Variant ◽

Tarsal Bones ◽

Mother And Daughter ◽

Dominant Disease ◽

History Of

Multicentric carpotarsal osteolysis syndrome (MCTO; MIM #166300) is a rare skeletal disorder characterized by osteolysis affecting particularly the carpal, metacarpal, and tarsal bones, although other bones might be involved. MCTO is an autosomal dominant disease caused by heterozygous variants in the <i>MAFB</i> gene, frequently misdiagnosed as juvenile rheumatoid arthritis due to similar clinical manifestations. This study reports the first Brazilian family diagnosed with MCTO with progressive osteolysis of the carpal and tarsal bones, presenting a c.161C>T (p.Ser54Leu) heterozygous variant in the <i>MAFB</i> gene, describing the clinical, radiological, and molecular findings, compared with literature data, and discussing the different clinical and molecular diagnosis, as well as the natural history of the disease. Since MCTO is a disorder with progressive symptoms, an early diagnosis is important to avoid unnecessary investigations and treatments and to provide the proper follow-up.

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A novel heterozygous variant inERLIN2causes autosomal dominant pure hereditary spastic paraplegia

European Journal of Neurology ◽

10.1111/ene.13625 ◽

2018 ◽

Vol 25 (7) ◽

pp. 943-e71 ◽

Cited By ~ 9

Author(s):

S. L. Rydning ◽

A. Dudesek ◽

F. Rimmele ◽

C. Funke ◽

S. Krüger ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Spastic Paraplegia ◽

Heterozygous Variant

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De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family

International Journal of Molecular Sciences ◽

10.3390/ijms22041549 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1549

Author(s):

Laura Castilla-Vallmanya ◽

Semra Gürsoy ◽

Özlem Giray-Bozkaya ◽

Aina Prat-Planas ◽

Gemma Bullich ◽

...

Keyword(s):

Autosomal Dominant ◽

De Novo ◽

Phenotypic Traits ◽

Gorlin Syndrome ◽

Consanguineous Family ◽

Indel Mutation ◽

Whole Exome ◽

Heterozygous Variant ◽

Skeletal Defects ◽

Turkish Family

We present a Turkish family with two cousins (OC15 and OC15b) affected with syndromic developmental delay, microcephaly, and trigonocephaly but with some phenotypic traits distinct between them. OC15 showed asymmetrical skeletal defects and syndactyly, while OC15b presented with a more severe microcephaly and semilobal holoprosencephaly. All four progenitors were related and OC15 parents were consanguineous. Whole Exome Sequencing (WES) analysis was performed on patient OC15 as a singleton and on the OC15b trio. Selected variants were validated by Sanger sequencing. We did not identify any shared variant that could be associated with the disease. Instead, each patient presented a de novo heterozygous variant in a different gene. OC15 carried a nonsense mutation (p.Arg95*) in PORCN, which is a gene responsible for Goltz-Gorlin syndrome, while OC15b carried an indel mutation in ZIC2 leading to the substitution of three residues by a proline (p.His404_Ser406delinsPro). Autosomal dominant mutations in ZIC2 have been associated with holoprosencephaly 5. Both variants are absent in the general population and are predicted to be pathogenic. These two de novo heterozygous variants identified in the two patients seem to explain the major phenotypic alterations of each particular case, instead of a homozygous variant that would be expected by the underlying consanguinity.

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A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability and structural brain abnormalities

10.21203/rs.3.rs-1074011/v1 ◽

2021 ◽

Author(s):

Nana Li ◽

Meixian Wang ◽

Yanna Zou ◽

Zhen Liu ◽

Ying Deng ◽

...

Keyword(s):

Intellectual Disability ◽

High Throughput Sequencing ◽

Autosomal Dominant ◽

Rare Variants ◽

Neurodevelopmental Disorder ◽

Zinc Ion ◽

Cognitive Capacity ◽

Chinese Family ◽

Prediction Tools ◽

Heterozygous Variant

Abstract Background Intellectual Disability (ID) is a characterized by significantly impaired adaptive behavior and cognitive capacity. Currently, high throughput sequencing approaches have led to the identification of genetic causes for ID in 25-50% of cases, while the causes of inherited ID are less well known. Here, we have investigated the genetic cause for non-syndromic ID in a Han Chinese family. Methods Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children as well as their asymptomatic parents. Data was filtered for rare variants and in silico prediction tools used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. Molecular modelling was conducted to establish the effects of the mutation on the protein encoded by a candidate coding gene. Results A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts the coordination of a zinc ion within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. Conclusions c.1323C>G mutation in ZBTB18 gene on 1 chromosome may be related with the phenotype of intellectual disability in this family. WGS is an efficient method to perform molecular diagnosis for hereditary ID. This is the first report of an inherited ZBTB18 mutation for ID and suggests that mutations that disrupt C2H2 motifs underlie human neurodevelopmental disorder.

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A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.720782 ◽

2021 ◽

Vol 9 ◽

Author(s):

Rinki Ratnapriya ◽

Samuel G. Jacobson ◽

Artur V. Cideciyan ◽

Milton A. English ◽

Alejandro J. Roman ◽

...

Keyword(s):

Retinal Degeneration ◽

Autosomal Dominant ◽

De Novo ◽

Causal Variant ◽

Unaffected Individual ◽

Retinal Degenerations ◽

Whole Exome ◽

Heterozygous Variant ◽

The Family ◽

Major Progress

Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.

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A Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review

BMC Endocrine Disorders ◽

10.1186/s12902-020-00666-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiu Zhao ◽

Zhuoguang Li ◽

Li Wang ◽

Zhangzhang Lan ◽

Feifei Lin ◽

...

Keyword(s):

Noonan Syndrome ◽

Autosomal Dominant ◽

Hormone Deficiency ◽

Chinese Family ◽

Sequencing Analysis ◽

Inherited Disease ◽

Case Presentation ◽

Multiple Systems ◽

Whole Exome ◽

Heterozygous Variant

Abstract Background Noonan syndrome is an inherited disease involving multiple systems. More than 15 related genes have been discovered, among which LZTR1 was discovered recently. However, the pathogenesis and inheritance pattern of LZTR1 in Noonan syndrome have not yet been elucidated. Case presentation We herein describe a family with LZTR1-related Noonan syndrome. In our study, the proband, sister, mother, maternal aunt and grandmother and female cousin showed the typical or atypical features of Noonan syndrome. Only 3 patients underwent the whole-exome sequencing analysis and results showed that the proband as well as her sister inherited the same heterozygous LZTR1 variant (c.1149 + 1G > T) from their affected mother. Moreover, the proband accompanied by growth hormone deficiency without other associated variants. Conclusion In a Chinese family with Noonan syndrome, we find that the c.1149 + 1G > T variant in LZTR1 gene shows a different autosomal dominant inheritance from previous reports, which changes our understanding of its inheritance and improves our understanding of Noonan syndrome.

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A novel frameshift MSX1 mutation in a Saudi family with autosomal dominant premolar and third molar agenesis

Archives of Oral Biology ◽

10.1016/j.archoralbio.2015.02.023 ◽

2015 ◽

Vol 60 (7) ◽

pp. 982-988 ◽

Cited By ~ 9

Author(s):

Shurog AlFawaz ◽

Vincent Plagnol ◽

Ferranti S.L. Wong ◽

David P. Kelsell

Keyword(s):

Autosomal Dominant ◽

Third Molar ◽

Third Molar Agenesis ◽

Saudi Family

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Autosomal Dominant Hypophosphatemic Rickets: A Case Report and Review of the Literature

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18168771 ◽

2021 ◽

Vol 18 (16) ◽

pp. 8771

Author(s):

Chiara Mameli ◽

Arianna Sangiorgio ◽

Valeria Colombo ◽

Mirko Gambino ◽

Luigina Spaccini ◽

...

Keyword(s):

Autosomal Dominant ◽

Late Onset ◽

Fibroblast Growth Factor 23 ◽

Failure To Thrive ◽

Spontaneous Remission ◽

Hypophosphatemic Rickets ◽

Autosomal Dominant Hypophosphatemic Rickets ◽

Heterozygous Variant ◽

Tubular Phosphate Reabsorption ◽

Phosphate Salts

Autosomal dominant hypophosphatemic rickets (ADHR) is an extremely rare form of genetic rickets caused by mutations in the fibroblast growth factor 23 gene. ADHR is characterized by hypophosphatemia secondary to isolated renal phosphate wasting. Only a few cases of ADHR have been reported in the literature to date. We describe the case of a 17-month-old girl who presented with severe failure to thrive (length: −4.08 standard deviation (SD), weight: −2.2 SD) and hypotonia. Hypophosphatemia, decreased tubular phosphate reabsorption (69%), and rachitic lesions were found. Genetic analysis showed the heterozygous variant c.536G>A (NM_020638.3:c.536G>A) in exon 3 of the FGF23 gene, leading to the diagnosis of ADHR. She was treated with phosphate salts and oral alfacalcidol. After 4 years of treatment, at 5 years of age, the patient’s ADHR resolved spontaneously. Considering the lack of knowledge regarding ADHR, we reviewed the literature to describe the features of this rare and poorly understood disease. Eleven ADHR pediatric cases have been described thus far, with cases tending to be more common in females than males. Similar to the general population, two groups of patients with ADHR can be described depending on the mutations present: patients with an R179 and R176 mutation have early-onset of disease and higher frequency of rickets, and a milder and late-onset of disease, respectively. Symptoms and disease severity may fluctuate. Spontaneous remission may occur during the pediatric age.

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The combined novel KCNQ1 frameshift I145Sfs*92 and nonsense W392X variants caused Jervell and Lange-Nielsen syndrome in a Chinese infant presenting with sustained foetal bradycardia

EP Europace ◽

10.1093/europace/euaa154 ◽

2020 ◽

Vol 22 (12) ◽

pp. 1880-1884

Author(s):

Yanmin Zhang ◽

Xiaomin Li ◽

Ying Yang ◽

Jie Wang ◽

Xinru Gao ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Dominant ◽

Autosomal Recessive Inheritance ◽

Autosomal Dominant Inheritance ◽

Incomplete Penetrance ◽

Recessive Inheritance ◽

Dominant Inheritance ◽

Heterozygous Variant ◽

Bilateral Sensorineural Hearing Loss ◽

Electrocardiogram Ecg

Abstract Aims We report clinical and molecular analysis of an infant presenting with foetal bradycardia and clinical outcome of Jervell and Lange-Nielsen syndrome (JLNS). Methods and results Clinical, electrocardiogram (ECG), and echocardiographic data were collected from members in a three-generation family. Whole exomes were amplified and sequenced for proband. The identified variants were verified in the remaining members. The pathogenicity of candidate variants was predicted using multiple software programmes. A 28-year-old non-consanguineous Chinese woman at 23 weeks’ gestation presenting with sustained foetal bradycardia of 100 b.p.m. Immunological disorders and infection were excluded. The infant was delivered at 37 weeks’ gestation with 2700-g birthweight. QTc was prolonged in both ECG and Holter recording. Hearing tests confirmed bilateral sensorineural hearing loss. Genetic testing demonstrated that the infant carried a novel frameshift c.431delC (p.I145Sfs*92) and a novel nonsense c.1175G>A (p.W392X) compound variants of KCNQ1 inherited from mother and father, respectively, in autosomal recessive inheritance. Only relative II-5 carrying heterozygous KCNQ1-I145Sfs*92 variant had prolonged QTc, while the other carriers did not have prolonged QT, suggesting an autosomal dominant inheritance of LQT1 phenotype with incomplete penetrance in the family. Conclusion We report the novel frameshift KCNQ1-I145Sfs*92 and nonsense KCNQ1-W392X compound variants in autosomal recessive inheritance that caused JLNS presenting as sustained foetal bradycardia for the first time. Meanwhile, KCNQ1-I145Sfs*92 heterozygous variant demonstrated LQT1 phenotype in autosomal dominant inheritance with incomplete penetrance.

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