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Human Molecular Genetics Aug 2023Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis...
Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple additional defects affecting the cranial region. These include orofacial clefts comprising midline cleft lip and palate and abnormalities of the craniofacial bones and frontal and/or basal encephalocele, in which brain tissue herniates through the cranium or into the nasal cavity. To investigate the causative mutation in the Grhl2Axd strain, whole genome sequencing identified an approximately 4 kb LTR retrotransposon insertion that disrupts the non-coding regulatory region, lying approximately 300 base pairs upstream of the 5' UTR. This insertion also lies within a predicted long non-coding RNA, oriented on the reverse strand, which like Grhl2 is over-expressed in Axd (Grhl2Axd) homozygous mutant embryos. Initial analysis of the GRHL2 upstream region in individuals with NTDs or cleft palate revealed rare or novel variants in a small number of cases. We hypothesize that mutations affecting the regulation of GRHL2 may contribute to craniofacial anomalies and NTDs in humans.
Topics: Animals; Humans; Mice; Abnormalities, Multiple; Cleft Lip; Cleft Palate; Encephalocele; Mutation; Neural Tube Defects; Spinal Dysraphism
PubMed: 37364051
DOI: 10.1093/hmg/ddad094 -
International Journal of Molecular... Jun 2021Defects in transcriptional and cell cycle regulation have emerged as novel pathophysiological mechanisms in congenital neuromuscular disease with the recent... (Review)
Review
Defects in transcriptional and cell cycle regulation have emerged as novel pathophysiological mechanisms in congenital neuromuscular disease with the recent identification of mutations in the and genes, encoding, respectively, ASC-1 and ASCC1, two subunits of the ASC-1 (Activating Signal Cointegrator-1) complex. This complex is a poorly known transcriptional coregulator involved in transcriptional, post-transcriptional or translational activities. Inherited defects in components of the ASC-1 complex have been associated with several autosomal recessive phenotypes, including severe and mild forms of striated muscle disease (congenital myopathy with or without myocardial involvement), but also cases diagnosed of motor neuron disease (spinal muscular atrophy). Additionally, antenatal bone fractures were present in the reported patients with mutations. Functional studies revealed that the ASC-1 subunit is a novel regulator of cell cycle, proliferation and growth in muscle and non-muscular cells. In this review, we summarize and discuss the available data on the clinical and histopathological phenotypes associated with inherited defects of the ASC-1 complex proteins, the known genotype-phenotype correlations, the ASC-1 pathophysiological role, the puzzling question of motoneuron versus primary muscle involvement and potential future research avenues, illustrating the study of rare monogenic disorders as an interesting model paradigm to understand major physiological processes.
Topics: Carrier Proteins; Congenital Abnormalities; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Multiprotein Complexes; Mutation; Neuromuscular Diseases; Transcription Factors
PubMed: 34204919
DOI: 10.3390/ijms22116039 -
Current Topics in Developmental Biology 2021Congenital birth defects result from an abnormal development of an embryo and have detrimental effects on children's health. Specifically, congenital heart malformations... (Review)
Review
Congenital birth defects result from an abnormal development of an embryo and have detrimental effects on children's health. Specifically, congenital heart malformations are a leading cause of death among pediatric patients and often require surgical interventions within the first year of life. Increased efforts to navigate the human genome provide an opportunity to discover multiple candidate genes in patients suffering from birth defects. These efforts, however, fail to provide an explanation regarding the mechanisms of disease pathogenesis and emphasize the need for an efficient platform to screen candidate genes. Xenopus is a rapid, cost effective, high-throughput vertebrate organism to model the mechanisms behind human disease. This review provides numerous examples describing the successful use of Xenopus to investigate the contribution of patient mutations to complex phenotypes including congenital heart disease and heterotaxy. Moreover, we describe a variety of unique methods that allow us to rapidly recapitulate patients' phenotypes in frogs: gene knockout and knockdown strategies, the use of fate maps for targeted manipulations, and novel imaging modalities. The combination of patient genomics data and the functional studies in Xenopus will provide necessary answers to the patients suffering from birth defects. Furthermore, it will allow for the development of better diagnostic methods to ensure early detection and intervention. Finally, with better understanding of disease pathogenesis, new treatment methods can be tailored specifically to address patient's phenotype and genotype.
Topics: Animals; Congenital Abnormalities; Genes; Genomics; Heart Defects, Congenital; Humans; Mutation; Phenotype; Xenopus laevis
PubMed: 34074532
DOI: 10.1016/bs.ctdb.2021.03.005 -
Journal of Medical Genetics Apr 2021BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the gene or 11p13 chromosomal aberrations...
BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher's exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the variants or 11p13 deletions with Benjamini-Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3'--regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.
Topics: Adolescent; Adult; Aniridia; Cataract; Child; Child, Preschool; Eye Abnormalities; Female; Genetic Association Studies; Genetic Predisposition to Disease; Glaucoma; Humans; Male; Mutation, Missense; PAX6 Transcription Factor; Pedigree; Young Adult
PubMed: 32467297
DOI: 10.1136/jmedgenet-2019-106172 -
Molecular Genetics & Genomic Medicine Jan 2024Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder that has been reported in all ethnicities, with several identifiable pathogenic variants. There...
INTRODUCTION
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder that has been reported in all ethnicities, with several identifiable pathogenic variants. There have been reported cases indicating that RTS may lead to low birth weight in fetuses, but specific data on the fetal period are lacking. Genetic testing for RTS II is currently carried out by identifying pathogenic variants in RECQL4.
METHODS
In order to determine the cause, we performed whole-genome sequencing (WGS) analysis on the patient and his parents. Variants detected by WGS were confirmed by Sanger sequencing and examined in family members.
RESULTS
After analyzing the WGS data, we found a heterozygous nonsense mutation c.2752G>T (p.Glu918Ter) and a novel frameshift insertion mutation c.1547dupC (p.Leu517AlafsTer23) of RECQL4, which is a known pathogenic/disease-causing variant of RTS. Further validation indicated these were compound heterozygous mutations from parents.
CONCLUSION
Our study expands the mutational spectrum of the RECQL4 gene and enriches the phenotype spectrum of Chinese RTS patients. Our information can assist the patient's parents in making informed decisions regarding their future pregnancies. This case offers a new perspective for clinicians to consider whether to perform prenatal diagnosis.
Topics: Humans; Rothmund-Thomson Syndrome; Mutation; Frameshift Mutation; Phenotype; China
PubMed: 38131666
DOI: 10.1002/mgg3.2347 -
Journal of Medical Genetics Jul 2022The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes...
BACKGROUND
The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far.
OBJECTIVE
We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques.
METHODS
Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families.
RESULTS
Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included , (), , , , , , , , and . Additionally, we detected a homozygous disease causing mutation in , as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in , , and .
CONCLUSIONS
Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.
Topics: Cohort Studies; Heart Defects, Congenital; Heterotaxy Syndrome; Homozygote; Humans; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Mutation; Exome Sequencing
PubMed: 34215651
DOI: 10.1136/jmedgenet-2021-107775 -
Progress in Retinal and Eye Research Jul 2023Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities... (Review)
Review
Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6-related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia. Therefore, the clinical recognition and differential genetic diagnosis of PAX6-related aniridia has been revealed to be much more challenging than initially thought, and still remains under-investigated. Here, we update specific clinical features of aniridia, with emphasis on their genotype correlations, as well as provide new knowledge regarding the PAX6 gene and its mutational spectrum, and highlight the beneficial utility of clinically implementing targeted Next-Generation Sequencing combined with Whole-Genome Sequencing to increase the genetic diagnostic yield of aniridia. We also present new molecular mechanisms underlying aniridia and aniridia-like phenotypes. Finally, we discuss the appropriate medical and surgical management of aniridic eyes, as well as innovative therapeutic options. Altogether, these combined clinical-genetic approaches will help to accelerate time to diagnosis, provide better determination of the disease prognosis and management, and confirm eligibility for future clinical trials or genetic-specific therapies.
Topics: Humans; PAX6 Transcription Factor; Aniridia; Eye Abnormalities; Mutation; Phenotype; Eye Proteins
PubMed: 36280537
DOI: 10.1016/j.preteyeres.2022.101133 -
American Journal of Medical Genetics.... Sep 2020To report ophthalmic findings of patients without colobomas, and with a clinical and molecular diagnosis of CHARGE Syndrome. Retrospective study of ophthalmic findings...
To report ophthalmic findings of patients without colobomas, and with a clinical and molecular diagnosis of CHARGE Syndrome. Retrospective study of ophthalmic findings in 67 CHARGE patients-clinically confirmed diagnosis with positive CHD7 mutation-seen in the Ophthalmology department of Cincinnati Children's Hospital Medical Center between January 1, 2008 through September 25, 2018. Criteria for inclusion in this study was absence of any form of a coloboma in either eye. In our cohort, all patients had a positive CHD7 mutation, in addition to a clinical diagnosis. 19.4% (13/67) of CHARGE patients did not have a coloboma in either eye. 69.2% (9/13) had strabismus, 76.9% (10/13) had a refractive error that warranted refractive correction, 23.1% (3/13) had amblyopia, 38.5% (5/13) had nasolacrimal duct obstruction, 30.8% (4/13) had dry eye syndrome and exposure keratopathy, 15.4% (2/13) had ptosis, 15.4% (2/13) had blepharitis, 15.4% (2/13) had Cortical Visual Impairment, 7.7% (1/13) of patients had optic nerve drusen, 7.7% (1/13) had Marcus Gunn Jaw Winking, and 7.7% (1/13) with an eyelid nevus. There are numerous ophthalmic findings in individuals with CHARGE Syndrome without colobomas. No study to date has evaluated the ophthalmic findings in CHD7 positive CHARGE patients without colobomas. These findings need to be assessed and treated to ensure optimal vision in the CHARGE patient population. Absence of coloboma does not rule out a diagnosis of CHARGE syndrome, and if there is a clinical suspicion, clinical confirmation then genetic testing would be warranted.
Topics: Adolescent; Blepharoptosis; CHARGE Syndrome; Child; Child, Preschool; Coloboma; DNA Helicases; DNA-Binding Proteins; Female; Heart Defects, Congenital; Humans; Infant; Jaw Abnormalities; Lacrimal Duct Obstruction; Male; Mutation; Nasolacrimal Duct; Nervous System Diseases; Optic Nerve; Reflex, Abnormal
PubMed: 32914532
DOI: 10.1002/ajmg.c.31840 -
Genes Mar 2021Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 () gene. It shows... (Review)
Review
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 () gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.
Topics: Blepharophimosis; Female; Forkhead Box Protein L2; Frameshift Mutation; Humans; Loss of Function Mutation; Male; Phenotype; Primary Ovarian Insufficiency; Protein Domains; Skin Abnormalities; Urogenital Abnormalities
PubMed: 33806295
DOI: 10.3390/genes12030364 -
American Journal of Medical Genetics.... Jan 2020Kabuki syndrome (KS) is a disorder of epigenetic dysregulation due to heterozygous mutations in KMT2D or KDM6A, genes encoding a lysine-specific methyltransferase or...
Kabuki syndrome (KS) is a disorder of epigenetic dysregulation due to heterozygous mutations in KMT2D or KDM6A, genes encoding a lysine-specific methyltransferase or demethylase, respectively. The phenotype is highly variable, including congenital cardiac and renal anomalies, developmental delay, hypotonia, failure to thrive, short stature, and immune dysfunction. All affected individuals have characteristic facial features. As KS natural history has not been fully delineated, limited information exists on its prenatal and perinatal history. Two tertiary centers collected retrospective data from individuals with KS (N = 49) using a questionnaire followed by review of medical records. Data from 49 individuals (age range: 7 months-33 years; 37% male; 36 with KMT2D mutations, 2 with KDM6A mutations, and 11 diagnosed clinically) were examined. Polyhydramnios affected 16 of 39 (41%) pregnancies. Abnormal quad screens in four out of nine (44%) pregnancies and reduced placental weights also complicated KS pregnancies. These data comprise the first large dataset on prenatal and perinatal history in individuals with confirmed (genetically or clinically) KS. Over a third of pregnancies were complicated by polyhydramnios, possibly secondary to abnormal craniofacial structures and functional impairment of swallowing. The differential diagnosis for polyhydramnios in the absence of intrauterine growth retardation should include KS.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; DNA-Binding Proteins; Diagnosis, Differential; Face; Female; Fetal Growth Retardation; Hematologic Diseases; Histone Demethylases; Humans; Infant; Male; Mutation; Neoplasm Proteins; Phenotype; Polyhydramnios; Pregnancy; Vestibular Diseases; Young Adult
PubMed: 31654559
DOI: 10.1002/ajmg.a.61387