scholarly journals ‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

2020 ◽  
Vol 182 (1) ◽  
pp. K1-K6 ◽  
Author(s):  
Yunting Lin ◽  
Yanna Cai ◽  
Jianan Xu ◽  
Chunhua Zeng ◽  
Huiying Sheng ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
De Novo ◽  
Hypophosphatemic Rickets ◽  
Dominant Inheritance ◽  
Germline Mosaicism ◽  
Pathogenic Variants ◽  
First Case ◽  
Heterozygous Variant ◽  
The Family ◽  
Normal Father

Objective X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR. Methods and results For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband. Conclusions This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

scholarly journals Analysis of Circadian Clock Gene BMAL1 in Pakistani Congenital Cataract Families

2018 ◽  
Author(s):  
Udita Bagchi ◽  
Shazia Micheal ◽  
Sorath Noorani Siddiqui ◽  
Muhammad Imran Khan ◽  
Marie-Paule Felder-Schmittbuhl ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Congenital Cataract ◽  
Gene Mutations ◽  
The Novel ◽  
Coding Region ◽  
Pathogenic Variants ◽  
Heterozygous Variant ◽  
The Family ◽  
Cataract Development

In mice, mutations or targeted disruptions of the core circadian gene Bmal1 have been implicated in early onset of ocular pathologies, including premature/congenital cataract development. The aim of the present study was to analyze probands of consanguineous Pakistani cataract families to identify the novel pathogenic variants in the BMAL1 gene. We have studied 21 congenital cataract families. Ophthalmic examination was performed for the probands and available family members. Genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing was performed for the entire coding region of the BMAL1 gene. Targeted Sanger sequencing of BMAL1 revealed a heterozygous variant c.41A>T; p.(Asp14Val) in one proband, but it did not co-segregate with the disease phenotype in the family. In addition, a nonsynonymous variant (rs2290037) was identified in five probands. Our study is the first one to analyze the role of BMAL1 gene mutations in humans for their association with congenital cataract. Although we were unable to find the variants associated with congenital cataract families from Pakistan, more studies from other populations will be informative to further prove the role of BMAL1 with the disease.

Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

2022 ◽  
pp. 097321792110688
Author(s):  
Francisco Ribeiro-Mourão ◽  
Ana Vilan ◽  
Sara Passos-Silva ◽  
Fernando Silveira ◽  
Miguel Leão ◽  
...  
Keyword(s):  
De Novo ◽  
Bone Fractures ◽  
Muscular Atrophy ◽  
Hip Dislocation ◽  
Arthrogryposis Multiplex Congenita ◽  
Pathogenic Variants ◽  
Genetic Abnormalities ◽  
Heterozygous Variant ◽  
Fetal Movements ◽  
Intrafamilial Variability

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C > T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.

scholarly journals Mutations in both SAMD9 and SLC19A2 genes caused complex phenotypes characterized by recurrent infection, dysphagia and profound deafness – a case report for dual diagnosis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yan Zhang ◽  
Yi Zhang ◽  
Victor Wei Zhang ◽  
Chunyi Zhang ◽  
Hongke Ding ◽  
...  
Keyword(s):  
De Novo ◽  
Vitamin B1 ◽  
Recurrent Infection ◽  
Multiple Organ ◽  
Growth Delay ◽  
Compound Heterozygous ◽  
Mendelian Disease ◽  
Pathogenic Variants ◽  
First Case ◽  
Low Incidence

Abstract Background Phenotypic difference is general in Mendelian disease. Due to the extremely low incidence for a single disease, phenotype spectrum needs to be expanded. Meanwhile, earlier knowledge says patients who suffered from two kinds of different Mendelian disease are very rare. Case presentation We describe a case of neonatal male with genital anomalies, growth delay, skin hyperpigmentation, chronic lung disease with recurrent infection, anemia, and severe deafness. Without any clear etiology after routine workflow, whole exome sequencing was carried on. A pathogenic de novo SAMD9 mutation and compound heterozygous likely-pathogenic variants in SLC19A2 were identified. Some symptoms were improved after the patient was treated with vitamin B1. Unfortunately, the boy died from sepsis and multiple organ failure before 1 year old. Conclusion Combining the phenotype and clinical progress of treatment, we report that it is the first case of a patient with both MIRAGE syndrome and TRMA syndrome.

A De Novo Mosaic PHEX Variant Causing Sporadic X-Linked Hypophosphatemic Rickets in a 2-Year-Old Girl

2021 ◽  
Author(s):  
Kok-Siong Poon ◽  
Karen Mei-Ling Tan ◽  
Margaret Zacharin ◽  
Cindy Wei-Li Ho
Keyword(s):  
De Novo ◽  
Sporadic Case ◽  
Hypophosphatemic Rickets ◽  
Genu Varum ◽  
Splice Donor ◽  
Mosaic Pattern ◽  
Pathogenic Variants ◽  
Phex Gene ◽  
History Of ◽  
Generation Sequencing

AbstractPathogenic variants in the PHEX gene are causative of X-linked hypophosphatemic rickets (XLH). We present a case of a 2-year-old girl with hypophosphatemic rickets with genu varum and short stature without any family history of XLH. Next generation sequencing of the PHEX gene identified a splice donor variant, NM_000444.6:c.1173 + 5G > A in intron 10. This variant had a mosaic pattern with only 22% of the sequence reads showing the variant allele and was not present in the girl's parents, both of whom had a normal phenotype. This is a sporadic case of a de novo mosaic splice-site variant in the PHEX gene.

scholarly journals Severe Generalized Epidermolysis Bullosa Simplex in Two Hong Kong Children due to De Novo Variants in KRT14 and KRT5

2020 ◽  
Vol 2020 ◽  
pp. 1-5 ◽  
Author(s):  
Shuk Ching Chong ◽  
Kam Lun Hon ◽  
Fernando Scaglia ◽  
Chung Mo Chow ◽  
Yu Ming Fu ◽  
...  
Keyword(s):  
Hong Kong ◽  
Epidermolysis Bullosa ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Recurrence Risk ◽  
Severe Form ◽  
Epidermolysis Bullosa Simplex ◽  
First Case ◽  
Heterozygous Variant ◽  
History Of

We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel de novo heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the KRT14 gene and the second case was due to a rare de novo heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the KRT5 gene. To our knowledge, the c.377T>G variant in the KRT14 gene has not been previously reported, and the c.527A>G variant in the KRT5 gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies.

scholarly journals Parental segregation study reveals rare benign and likely benign variants in a Brazilian cohort of rare diseases

2021 ◽  
Author(s):  
Caio Robledo Quaio ◽  
Jose Ricardo Magliocco Ceroni ◽  
Murilo Castro Cervato ◽  
Helena Strelow Thurow ◽  
Caroline Monaco Moreira ◽  
...  
Keyword(s):  
Rare Diseases ◽  
Segregation Analysis ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
De Novo ◽  
Molecular Data ◽  
Autosomal Dominant Inheritance ◽  
Dominant Inheritance ◽  
Pathogenic Variants ◽  
Genomic Studies

Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases. This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a “de novo” event was expected. Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign (n=51) and 211 as likely benign (n=211). In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.

scholarly journals Analysis of the Genetic Characteristics of a Chinese Family With Otosclerosis

2020 ◽  
pp. 014556132091062
Author(s):  
Yongli Zhang ◽  
Qi Tang ◽  
Ruoyan Xue ◽  
Xiaohui Zhu ◽  
Hua Yang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Autosomal Dominant ◽  
Family Members ◽  
Autosomal Dominant Inheritance ◽  
Dominant Inheritance ◽  
Genetic Characteristics ◽  
Whole Exome ◽  
The Family

Background: Otosclerosis is a focal lesion of the inner ear. The role of genetic factors in the pathogenesis of otosclerosis has received increasing attention. We analyzed the clinical manifestations, inheritance pattern, and pathogenic genes in a family with otosclerosis. Methods: We collected clinical data and generated a family pedigree. High-throughput second-generation sequencing technology was used to identify candidate genes by performing whole-exome sequencing of 7 members of the family, and Sanger sequencing was performed to validate candidate gene mutations in the 7 family members. Results: Otosclerosis was characterized by autosomal dominant inheritance in this family. Whole-exome sequencing did not reveal mutation sites in known deafness-related genes. However, a c.2209A > G (p.T737A) mutation was detected in exon 6 of the SP1 gene, which is associated with the COL1A1 gene. This mutation was a pathogenic mutation, and Sanger sequencing confirmed that this mutation cosegregated with the clinical phenotype among the family members. Conclusions: The pattern of otosclerosis in this family is consistent with autosomal dominant inheritance, and the SP1 gene, harboring the c.2209A > G (p.T737A) mutation in exon 6, may be the causative gene of otosclerosis in this family.

scholarly journals Somatic and Germline Mosaicism for a Mutation of the PHEX Gene Can Lead to Genetic Transmission of X-Linked Hypophosphatemic Rickets That Mimics an Autosomal Dominant Trait

2006 ◽  
Vol 91 (2) ◽  
pp. 365-370 ◽  
Author(s):  
Katsumi Goji ◽  
Kayo Ozaki ◽  
Ahmad H. Sadewa ◽  
Hisahide Nishio ◽  
Masafumi Matsuo
Keyword(s):  
Autosomal Dominant ◽  
Molecular Genetic ◽  
Autosomal Dominant Inheritance ◽  
Hypophosphatemic Rickets ◽  
Nucleotide Sequencing ◽  
Dominant Inheritance ◽  
Dominant Trait ◽  
Autosomal Dominant Trait ◽  
Germline Mosaicism ◽  
Genetic Transmission

Context: Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. Objective: The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. Patients: We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. Methods and Results: Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. Conclusions: Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

scholarly journals A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1395
Author(s):  
Valentina Bruni ◽  
Cristina Barbara Spoleti ◽  
Andrea La Barbera ◽  
Vincenzo Dattilo ◽  
Emma Colao ◽  
...  
Keyword(s):  
Skeletal Dysplasia ◽  
Messenger Rna ◽  
De Novo ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Splicing Variant ◽  
Pathogenic Variants ◽  
Heterozygous Variant ◽  
Achondrogenesis Type ◽  
Kniest Dysplasia

Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia.

scholarly journals KAT6B-related disorder in a patient with a novel frameshift variant (c.3925dup)

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Yo Hamaguchi ◽  
Mikihiro Aoki ◽  
Satoshi Watanabe ◽  
Hiroyuki Mishima ◽  
Koh-ichiro Yoshiura ◽  
...  
Keyword(s):  
Japanese Patient ◽  
De Novo ◽  
Proximal Region ◽  
Rare Disorders ◽  
Related Disorder ◽  
Pathogenic Variants ◽  
Heterozygous Variant ◽  
Lysine Acetyltransferase

AbstractHeterozygous pathogenic variants in the KAT6B gene, which encodes lysine acetyltransferase 6B, have been identified in patients with congenital rare disorders, including genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome. Herein, we report another Japanese patient with a KAT6B-related disorder and a novel de novo heterozygous variant in exon 18 of KAT6B [c.3925dup, p.(Glu1309fs*33)], providing further evidence that truncating variants in exon 17 and in the proximal region of exon 18 are associated with genitopatellar syndrome-like phenotypes.

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