Figure 1 - uploaded by Jin Wang
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Characteristic facial feature of the patient. A and B are the front and side views of the patient. Notable features include ocular hypertelorism, dystopia canthorum, short philtrum and wide based nose root with hypoplasia alae nasi.
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Waardenburg syndrome type I (WS1), an auditory-pigmentary genetic disorder, is caused by heterozygous loss-of-function mutations in PAX3. Abnormal physical signs such as dystopia canthorum, patchy hypopigmentation and sensorineural hearing loss are common, but short stature is not associated with WS1.
We reported a 4-year and 6 month-old boy with a...
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This paper deals with the molecular investigation of Waardenburg syndrome (WS) in a sample of 49 clinically diagnosed probands (most from southeastern Brazil), 24 of them having the type 1 (WS1) variant (10 familial and 14 isolated cases) and 25 being affected by the type 2 (WS2) variant (five familial and 20 isolated cases). Sequential Sanger sequ...
Waardenburg syndrome (WS) is an autosomal dominant inherited neurogenic disorder with the combination of various degrees of sensorineural deafness and pigmentary abnormalities affecting the skin, hair and eye. The four subtypes of WS were defined on the basis of the presence or absence of additional symptoms. Mutation of human microphthalmia-associ...
Purpose:
Waardenburg syndrome (WS) is a rare condition characterized by six main features. It has been previously observed that WS is also associated with hypopigmentation of the choroid through multimodal imaging. To our knowledge, this is the first report of using swept-source optical coherence tomography angiography (OCTA) on a patient with kno...
Citations
... 26 A model other than haploinsufficiency may have to be involved because this patient does not have the short stature reported in those with contiguous gene deletions involving EPHA4 (ref. 27 ). Epha4-deficient mouse models demonstrate a unique "hopping gait" overlapping with the lower limb involvement and abnormal gait observed in this patient. ...
The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP).
Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis.
A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%).
NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.
... Various types of gene mutations have been associated with WS, including small indels, point mutations, and large deletions (Doubaj et al., 2015;Li et al., 2015;Cortes-Gonzalez et al., 2016). Sanger sequencing is generally used for the genetic diagnosis of WS; however, using this approach to study WS, which is a genetically heterogeneous disorder, is laborious. ...
Objectives:
Waardenburg syndrome (WS) is a rare autosomal dominant disorder associated with pigmentation abnormalities and sensorineural hearing loss. In this study, we investigated the genetic cause of WSII in a patient and evaluated the reliability of the targeted next-generation exome sequencing method for the genetic diagnosis of WS.
Methods:
Clinical evaluations were conducted on the patient and targeted next-generation sequencing (NGS) was used to identify the candidate genes responsible for WSII. Multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative polymerase chain reaction (qPCR) were performed to confirm the targeted NGS results.
Results:
Targeted NGS detected the entire deletion of the coding sequence (CDS) of the SOX10 gene in the WSII patient. MLPA results indicated that all exons of the SOX10 heterozygous deletion were detected; no aberrant copy number in the PAX3 and microphthalmia-associated transcription factor (MITF) genes was found. Real-time qPCR results identified the mutation as a de novo heterozygous deletion.
Conclusions:
This is the first report of using a targeted NGS method for WS candidate gene sequencing; its accuracy was verified by using the MLPA and qPCR methods. Our research provides a valuable method for the genetic diagnosis of WS.
... Örneğin, Waardenburg sendromuna(OMIM 193500) sebep olduğu bilinen 2q35p36.2 delesyonunun, bu bölgede bulunan EPHA4 geninin haplo yetersizliğine bağlı olarak boy kısağına yol açtığı gösterilmiştir [94]. Son yapılan çalışmalarda idiyopatik kısa boy teşhisi konulmuş hastaların %10'unda hastalığa sebep olduğu düşünülen kopya sayısı değişikliğine rastlanmıştır [95][96][97][98]. ...
... The manner of inheritance is autosomal dominant and covers 2–5 % of all congenital deafness. Children with this syndrome may have changes in iris pigmentation or hair; sometimes striking blue or prematurely gray (Jang et al., 2015; Li et al., 2015). ...
Hearing impairment is the most conjoint sensory debit in humans which include perturbations due to both environmental factors and genetic causes, with changeable times of onset ranging from congenital deafness to presbycusis. A hearing defect beginning in early childhood has dramatic effects on speech acquisition and psychosocial development. Later onset of a hearing defect seriously compromises the subject’s quality of life as the affected individual becomes increasingly socially isolated. About 1 in 1000 children become severe to profound deaf before adulthood. More than 100 loci and 49 casually concerned genes are identified for monogenic hearing loss. About 70% of hereditary hearing impairment cases are classified as non-syndromic deafness (isolated hearing loss) and 30% as syndromic deafness (hearing loss with other anomalies). The mode of inheritance of non-syndromic hearing impairment is autosomal recessive (80%), autosomal dominant (20%), X-linked (1%) and mitochondrial (<1%). Non-syndromic hearing impairment is highly heterogeneous and about 50% of prelingual autosomal recessive hearing impairment is caused by mutation on the DFNB1 locus harboring GJB2 gene. More than 400 genetic syndromes that include deafness are defined and estimated to be account for 30% of prelingual deafness. In the present study, three families with autosomal recessive syndromic hearing impairment (A, B, D) and one family (C) with autosomal recessive non-syndromic hearing impairment were ascertained from different regions of Pakistan. Family C establish linkage to the gene ESRRB on chromosome 14q24.3. However, sequence analysis failed to identify potential sequence variants in the gene ESRRB in DNA of the affected individuals. In rest of three families (A, B, D), genotyping by polymorphic microsatellite markers revealed that affected individuals were heterozygous for different combinations of parental alleles, thus excluding the linkage in these families to the established hearing impairment candidate regions.
Background: Deletions of the interstitial 2q36 are uncommon and associated with varying phenotypes. However, the list of currently known phenotypes is still far complete for an understanding of the interstitial 2q36 deletion syndrome characteristics.
Aims/Objectives: To identify the genetic and clinical characterization of a 6-year-old male patient suffering from a severe form of syndromic hearing loss, with brachydactyly family history.
Material and Methods: We performed conventional cytogenetic analysis on the peripheral blood lymphocytes and whole exome sequencing and SNP array analysis on DNA samples from the family.
Results: The proband showed signs such as bilateral sensorineural deafness, ocular hypertelorism, flat facial profile and several decayed teeth, slightly ulnar deviation of the hands, single transverse palmar crease, short stature and intellectual disability. Through cytogenetic and molecular genetic analysis, we discovered that the syndromic hearing loss was the result of a de novo 5.175-Mb microdeletion at chromosome 2q36.1q36.3 whose breakpoints had been precisely mapped by us.
Conclusions and Significance: Our study warns that auditory assessment should be evaluated even if the patient with 2q36 deletion syndrome is not obviously presenting hearing loss. In addition, a comprehensive molecular genetics diagnosis involving multiple methods is important to support accurate genetic characterization of this syndrome.
Melanocyte development is orchestrated by a complex interconnecting regulatory network of genes and synergistic interactions. Piebaldism and Waardenburg syndrome are neurocristopathies that arise from mutations in genes involved in this complex network. Our understanding of melanocyte development, Piebaldism, and Waardenburg syndrome has improved dramatically over the past decade. The diagnosis and classification of Waardenburg syndrome, first proposed in 1992 and based on phenotype, have expanded over the past three decades to include genotype. This review focuses on the current understanding of human melanocyte development and the evaluation and management of Piebaldism and Waardenburg syndrome. Management is often challenging and requires a multidisciplinary approach.
The fast technological development, particularly SNP array, array-comparative genomic hybridization and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways and fundamental cellular processes, followed by chromosomal aberrations including copy number variants and imprinting disorders associated with short stature. Many novel causes of growth hormone (GH) deficiency as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GH deficiency are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3 and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in approximately 3% of short children, and also rasopathies (e.g. Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, copy number variants and imprinting disorders.
Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-I defect may modestly decrease height and head circumference.
The objective of the study was to investigate the clinical features of heterozygous carriers of a novel mutation in the IGF1 gene in comparison with noncarriers in a short family and to establish the effect of human GH treatment.
Two children, their mother, and their maternal grandfather carried the mutation and were compared with two relatives who were noncarriers.
The two index cases had severe short stature (height sd score -4.1 and -4.6), microcephaly, and low IGF-I levels. Sequencing of IGF1 revealed a heterozygous duplication of four nucleotides, resulting in a frame shift and a premature termination codon. The mother and maternal grandfather had the same IGF1 mutation. Adult height (corrected for shrinking and secular trend) and head circumference sd score of carriers of the paternally transmitted mutation was -2.5 and -1.8, in comparison with -1.6 and 0.3 in noncarriers, respectively. After 2 yr of GH treatment, both index cases exhibited increased growth.
Heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH.
