Hearing loss is one of the most common symptoms of mitochondrial disorders. However, audiological phenotypes associated with different molecular defects in mtDNA are not yet well characterized.
A ...large cohort of 1499 nonconsanguineous patients aged 5-40 years with hearing loss of unknown etiology was screened for mutations in mtDNA. For further analysis, patients harboring m.1555A>G and m.3243A>G were selected. Hearing status of the patients was assessed by pure tone audiometry. Patterns of audiograms (hearing threshold levels at each examined frequency) were statistically compared among the carriers of the m.1555A>G and the m.3243A>G mutations.
We identified 20 patients positive for m.1555A>G mutation and 16 patients positive for m.3243A>G change. The frequency of the above transitions was calculated in our cohort as 1.33% and 1.06%, respectively. Seventeen affected family members carrying the mutations were included into the study. Typical shape of the audiograms in patients with m.1555A>G mutation presented a ski-slope pattern, whereas the audiometric curves among the m.3243A>G individuals had a pantonal shape (a flat curve) with slight downward sloping at the higher frequencies. The differences were statistically significant. The onset of hearing loss was noted earlier among m.1555A>G than m.3243A>G patients (12.5 and 26 years, respectively). Aminoglycoside administration was declared in both groups in 11 and 4 cases respectively, and caused abrupt hearing deterioration in all cases.
A pattern of audiogram in patients with mitochondrial deafness may suggest a localization of mtDNA mutation. The pathogenesis of the audiometric differences needs further study.
Cornelia de Lange syndrome (CDLS) is a clinically and genetically heterogeneous developmental disorder characterized by multiple malformations. Primarily, affected individuals have unique and ...recognizable dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. However, also milder, as well as slightly phenotypically different forms exist. We described herein a patient with CDLS5, an X-linked form, caused by mutations in the HDAC8 gene inherited form the mosaic mother. Analysis of results from whole exome sequencing identified two variants with possible impact on the phenotype. Of them, hemizygous variant (c.938G>A, p.Arg313Gln) inherited from the mosaic mother, was further proved to lead to disease in the proband. Our intention was to delineate this syndrome but also point out the clinical course of the disease, which only in combination with a facial phenotype allow for verification of exome sequencing result.
Holt–Oram syndrome (HOS) features radial ray hypoplasia, heart defect and cardiac conduction impairment. Ulnar-mammary syndrome (UMS) characterizes congenital defects of the ulnar side of the upper ...limbs, underdevelopment of apocrine glands including hypoplasia and the dysfunction of mammary glands, hypogonadism and obesity. Inheritance of both conditions is autosomal dominant, mutations or deletions are found in the
TBX5
and
TBX3
gene, respectively. The Polish patient presented short stature, obesity, congenital malformation of the radial and ulnar side of the upper limbs, heart block, hypogonadism and dysmorphic features. At the age of 13 years he lost consciousness developing respiratory insufficiency caused by bradycardia in the course of sudden atrioventricular third degree heart block requiring immediate implantation of pace maker-defibrillator device. Microdeletion of the 12q24.21 was identified using array CGH method. This region includes contiguous genes the
TBX5, TBX3
, and part of
RBM19.
The patient initially diagnosed as having HOS, was found to present the UMS features as well. Array CGH method should be applied in patients suspected of HOS or UMS, especially when sequencing of
TBX5
or
TBX3
genes fails to identify causative mutation.
•CPC patients harbor germline TP53 mutations, but none of them was described as a mosaic mutation.•We present 1.5 year old patient with bilateral disseminated CPC harboring de novo TP53 mosaic ...mutation.•Our results highlight the utility of NGS technology in detection of mosaicism.
Choroid plexus tumors (CPT) constitute 2%–5% of all pediatric brain tumors and include high grade choroid plexus carcinoma (CPC). About 40% of CPC patients harbor germline TP53 mutations, associated with diminished survival rates. However, the number of TP53 carriers might be underestimated due to suboptimal ability of Sanger sequencing to identify mosaicism. We describe an 18-month-old boy with ultra-rare, bilateral disseminated CPC and negative family history of cancer. Next generation sequencing (NGS) revealed constitutional mosaicism of de novo TP53 mutation, which was barely detectable by Sanger sequencing. This is the first description of a de novo TP53 mutation mosaicism in a patient with CPC. Up to now four cases of de novo TP53 mutations in CPC patients have been described but none of them were mosaic. Since TP53 mutation mosaicism may have an impact on management of patients and predisposition to other cancers, a reliable method of identification is important. Our results highlight the utility of high-throughput technologies in detection of potentially important genetic markers.
The prevalence of isolated hearing loss (HL) associated with the m.3243A>G mutation is unknown. The aim of this study was to assess the frequency and heteroplasmy level of the m.3243A>G mutation in a ...large group of Polish patients with postlingual bilateral sensorineural HL of unidentified cause. A molecular search was undertaken in the archival blood DNA of 1482 unrelated patients with isolated HL that had begun at ages between 5 and 40 years. Maternal relatives of the probands were subsequently investigated and all carriers underwent audiological tests. The m.3243A>G mutation was found in 16 of 1482 probands (an incidence of 1.08%) and 18 family members. Of these 34 individuals, hearing impairment was detected in 29 patients and the mean onset of HL was at 26 years. Some 42% of the identified m.3243A>G carriers did not develop multisystem symptomatology over the following 10 years. Mean heteroplasmy level of m.3243A>G was lowest in blood at a level of 14% and highest in urine at 58%. These values were independent of the manifested clinical severity of the disease. A single m.3243A>G carrier can usually be found among each 100 individuals who have postlingual hearing loss of unknown cause. Urine samples are best for detecting the m.3243A>G mutation and diagnosing mitochondrially inherited hearing loss.
Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our ...purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5-8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n = 302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p = 0.0013, p(cor.) = 0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio = 4.88, p = 0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation-an intervention which is simple, cheap, and devoid of side effects.
SCO2 mutations cause recessively inherited cytochrome c oxidase deficiency. Recently Tran-Viet et al. proposed that heterozygosity for pathogenic SCO2 variants, including the common E140K variant, ...causes high-grade myopia. To investigate the association of SCO2 mutations with myopia, ophthalmic examinations were performed on 35 E140K carriers, one homozygous infant, and on a mouse model of Sco2 deficiency. Additionally, a screen for other putative effects of SCO2 heterozygosity was carried out by comparing the prevalence of the common E140K variant in a population of patients with undiagnosed diseases compatible with SCO2-related pathogenesis to that in a general population sample. High-grade myopia was not identified in any of the studied individuals. Of the carriers, 17 were emmetropic, and 18 possessed refractive errors. Additionally, no significant axial elongation indicative of high-grade myopia was found in mice carrying E129K (corresponding to E140K in humans) knock-in mutations. The prevalence of E140K carriers in the symptomatic cohort was evaluated as 1:103 (CI: 0.44–2.09) and did not differ significantly from the population prevalence (1:147, CI: 0.45–1.04).
Our study demonstrates that heterozygosity for pathogenic SCO2 variants is not associated with high-grade myopia in either human patients or in mice.
Diagnoses of hypoacousis in children based on behavioral examination in 60-ies brought about the idea of creation recommendation for hearing screening program in children. Joint Committee of Infant ...Hearing, organized in US in early 70-ies by the speech and hearing therapists, has edited several recommendations concerning hearing screening in children. The point of view on this problem has been changing with the development of new techniques and increase of knowledge. Initially, hearing screening was introduced only in children of high risk population. Nationals Institutes of Health, another American organization created in 90-ies, has edited details concerned implementation of the universal hearing screening program. The idea to introduce this program has expand from the USA to Europe. The document European Consensus established in 1998 regulates the status of nationals programs of universal hearing screening which are widely implemented to the clinical practice.
Polish National Universal Hearing Screening Program (PNPUHS) has got three-level structure. Audiology Outpatient Clinic in The Childrens' Memorial Health Institute in Warsaw is a center of the second ...and the third level. Newborns are referred to us from neonatal units, the first level in the program. We found that referred children, both with unilateral as well as bilateral referral rating in TEOAE, show a high proportion of false positive results.
To analyze a diagnostic process of healthy neonates referred to our Audiology Outpatient Clinic with referral rating in one and both ears measured by TEOAE in 2005 and 2006. Assessed parameters include: attendance of patients to further diagnostics tests, with respect to their results, specificity and sensitivity of methods: TEOAE, DPOAE, analysis of final diagnoses of hearing loss.
1764 infants without risk factors of hearing loss, aged from one to six months referred with referral rating in one or both ears in TEOAE.
Diagnostics methods include: otoscopy, DPOAE, AI, BOA. Incorrect results are indication for ABR examination, if not conclusive ASSR. Collected data were statistically analyzed by chi-squared test and Czupurow and V-Cramer coefficient.
998 (56,5%) of 1764 examined children passed DPOAE. Only 512 (66,8%) of remaining 766 neonates carried on further investigations. Diagnosis of hearing loss was made in 449 patients (25%), including 320 (71%) with bilateral and 129 (29%) with unilateral involvement. Sensorineural hearing loss was detected in 274 children (61%), conductive in 161 (35,8%), and mixed in 14 patients (3,1%). Global PNUHSP specificity are 95,45% and sensitivity results are 95,08% respectively. Although in our Audiology Outpatient Clinic, sensitivity rate of TEOAE and DPOAE is 94,5%, and 94,4% respectively, the specificity rate of TEOAE appeared to be 36,9% and of DPOAE 79,7%.
Universal newborn hearing screening program permit early diagnosis and intervention in neonates and infants before 6th month of age. High rate of specificity and sensitivity characterizes the Polish Program. Low rate of specificity detected in our outpatient clinic indicates the necessity to effect and cost analysis in neonatal units. Comparison of two groups with bilateral and unilateral referral rating in screening shows that higher number of patients follow diagnostic process from the group with bilateral incorrect results, more diagnoses of hearing loss was established in this group as well.
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