<scp><i>TUBB3</i> E410K</scp> syndrome: Case report and review of the clinical spectrum of <scp><i>TUBB3</i></scp> mutations

Dentici, Maria Lisa; Maglione, Vittorio; Agolini, Emanuele; Catena, G.; Capolino, Rossella; Lanari, Valentina; Novelli, Antonio; Sinibaldi, Lorenzo; Vecchio, Davide; Gonfiantini, Michaela Veronika; Macchiaiolo, Marina; Digilio, Maria C.; Dallapiccola, Bruno; Bartuli, Andrea

doi:10.1002/ajmg.a.61719

Cited by 15 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Suspicion of the presence of a CNS anomaly was first raised at ultrasound screening, at a mean gestational age of 24.2 (range, [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] weeks, due to one or more of the following findings: midline abnormality, including of the corpus callosum (n = 19 (55.9%)), abnormal ventricles (n = 18 (52.9%)), abnormal posterior fossa (n = 4 (11.8%)), abnormal sulcation (n = 4 (11.8%)) and/or family history (n = 5 (14.7%)). In 38% of cases, there was more than one of these findings.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Spectrum of brain malformations in fetuses with mild tubulinopathy

Hagege

Haratz

Malinger

et al. 2023

Ultrasound in Obstet & Gyne

View full text Add to dashboard Cite

Objective To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can facilitate prenatal diagnosis. Methods This was a retrospective multicenter study of fetuses diagnosed between January 2007 and February 2022 with a mild tubulinopathy (without lissencephaly or microlissencephaly). We collected and reviewed brain imaging and genetic data, and defined major criteria as findings observed in ≥ 70% of the patients and minor criteria as those observed in ≥ 50% but < 70% of the patients. Results Our cohort included 34 fetuses. The mean gestational age at ultrasound screening, when suspicion of a central nervous system anomaly was first raised, was 24.2 (range, 17–33) weeks. Callosal anomalies (n = 19 (56%)) and abnormal ventricles (n = 18 (53%)) were the main reasons for referral. The mean gestational age at neurosonography was 28.3 (range, 23–34) weeks and that at MRI was 30.2 (range, 24–35) weeks. Major ultrasound criteria were midline distortion, ventricular asymmetry, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation. Minor ultrasound criteria were distortion of the cavum septi pellucidi, abnormal corpus callosum, absent or asymmetric olfactory sulci, ventriculomegaly and basal ganglia dysmorphism. Major MRI criteria were midline distortion, distortion of the cavum septi pellucidi, ventricular asymmetry, dilatation (generally unilateral) and/or distortion, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation (mainly dysgyria). Minor MRI criteria were absent or asymmetric olfactory sulci, abnormal bulge of the pons, anteroposterior diameter of the pons ≤ 5th centile and brainstem asymmetry. A mutation was found in TUBB3 (44.1% of cases), TUBB (23.5%), TUBB2B (14.7%) or TUBA1A (17.6%). The mutation was inherited from a parent in 18/34 cases. The pregnancy was terminated in 23/34 cases. Conclusions Prenatal diagnosis of mild forms of tubulinopathy is possible but challenging. We have defined, in this large series of fetuses, major and minor criteria that can help identify this entity in utero. Most findings can be visualized on ultrasound. This evaluation is also important for prenatal counseling. Once a prenatal diagnosis of mild tubulinopathy is suspected, the family members should be referred for exome sequencing and MRI. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Hypoplasia or absence of the olfactory bulbs and sulci are typical findings of tubulinopathy 2,3,16,17,[19][20][21][22] . In our series, analysis of these structures was not relevant in many cases due to the early gestational age [23][24][25] or to poor visualization in our retrospective analysis.…”

Section: Discussionmentioning

confidence: 99%

Spectrum of brain malformations in fetuses with mild tubulinopathy

Hagege

Haratz

Malinger

et al. 2023

Ultrasound in Obstet & Gyne

View full text Add to dashboard Cite

show abstract

“…The mouse model for OTC deficiency has decreased mitochondrial complex IV activity, decreased mitochondrial detoxification capacity, and reduced ATP levels in brain ( 54 ). Two specific variants in TUBB3 , E410K ( 55 ) and R262H ( 56 ) have been reported in 5 and 3 cases with paroxysmal vomiting, respectively. TUBB3 encodes for beta-tubulin, a microtubule component that enables anterograde mitochondrial transport along axons.…”

Section: Discussionmentioning

confidence: 99%

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Bar¹,

Ebenau²,

Weiner³

et al. 2023

Front. Neurol.

View full text Add to dashboard Cite

ObjectiveTo utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting.MethodsA retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. “Qualifying” variants were defined as coding, rare, and conserved. Additionally, “Key Qualifying” variants were Pathogenic/Likely Pathogenic, or “Clinical” based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system.ResultsThirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as “Highly likely” (SCN4A, CACNA1A, CACNA1S, RYR2, TRAP1, MEFV) or “Likely” (SCN9A, TNFRSF1A, POLG, SCN10A, POGZ, TRPA1) CVS related. Nine additional genes (OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3, PPM1D, CHAMP1, HMBS) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant (p < 0.0001, p = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, post-analyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as “Possibly” CVS related.ConclusionAll 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the non-paroxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS.

show abstract

“…Hypogonadotropic hypogonadism may occur isolated or in association with anosmia or hyposmia, known as Kallmann syndrome (OMIM #308700) ( Dwyer et al, 2023 ). The advent of high-throughput sequencing techniques has led to the understanding of the genetic basis of hypogonadotropic hypogonadism in patients with complex syndromes, such as CHARGE syndrome (OMIM #214800) due to CHD7 variants, Waardenburg syndrome (OMIM #613266) associated with SOX10 mutations, TUBB3 syndrome (OMIM #600638) due to E410K mutation in TUBB3 ( Dentici et al, 2020 ), and Pallister–Hall syndrome (OMIM #146510) caused by mutations in GLI3 ( Grinspon, 2022 ). In many of these syndromes, the reproductive phenotype remains underdiagnosed, with the clinical focus driven to the complex symptomatology.…”

Section: Introductionmentioning

confidence: 99%

Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen–Kolk syndrome

Correa Brito,

Keselman,

Villegas

et al. 2024

Front. Genet.

View full text Add to dashboard Cite

Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic hypogonadism has been suggested to overlap with Witteveen–Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions encompassing SIN3A. Whether hypogonadotropic hypogonadism is due to haploinsufficiency of SIN3A or any of the other eight genes present in 15q24 is not known. We report the case of a female patient with delayed puberty associated with intellectual disability, behavior problems, dysmorphic facial features, and short stature, at the age of 14 years. Clinical, laboratory, and imaging assessments confirmed the diagnosis of Kallmann syndrome. Whole-exome sequencing identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016Argfs*6) in SIN3A, classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG/AMP) criteria. Reverse phenotyping led to the clinical diagnosis of WITKOS. No other variant was found in the 96 genes potentially related to hypogonadotropic hypogonadism. The analysis of the other contiguous seven genes to SIN3A in 15q24 did not reveal any clinically relevant variant. In conclusion, these findings point to SIN3A as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome.

show abstract

TUBB3 E410K syndrome: Case report and review of the clinical spectrum of TUBB3 mutations

Cited by 15 publications

References 18 publications

Spectrum of brain malformations in fetuses with mild tubulinopathy

Spectrum of brain malformations in fetuses with mild tubulinopathy

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen–Kolk syndrome

Contact Info

Product

Resources

About