Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known ...disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.
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•Multiplex consanguineous families are rich sources for novel gene discovery•Prescreening these families for known disease genes accelerates gene discovery•33 novel candidate genes are reported in this study
Using whole-exome sequencing on prescreened multiplex consanguineous families, Alazami et al. describe the identification of 33 novel candidate genes for various neurogenetic conditions. Such families are rich sources for novel gene discovery.
TCF4 gene encodes a class I helix–loop–helix transcription factor critical for the developing brain. Common polymorphisms in TCF4 and disruptive variants in the proximal region of the gene have been ...linked to relatively mild neuropsychiatric or neurodevelopmental disorders. In contrast, variants impacting distal exons are associated with Pitt–Hopkins syndrome (PTHS), a severe autosomal dominant condition characterized by profound intellectual disability, developmental delay, limited or absent speech, distinctive facies, and disordered breathing. Although phenotypic variability has been observed in PTHS, intellectual impairment and significant speech and motor delays are invariably present. In contrast to the typical de novo variants causing TCF4‐related disorder and PTHS, we report a familial form of TCF4‐related disorder where the missense variant arose de novo in the father and was inherited by two of his children. Although this family's variant's position in exon 18 predicted a typical PTHS phenotype, none of the affected individuals met the clinical diagnostic criteria for PTHS suggested by Zollino et al. in the first international consensus statement (as in the study by Zollino et al. in 2019). Rather, the three affected family members exhibited remarkably variable and milder phenotypes than would have been predicted from the position of their TCF4 variant. Thus, the clinical spectrum of PTHS‐associated TCF4 variants may be broader than previously reported.
Abstract
TCF4
gene encodes a class I helix–loop–helix transcription factor critical for the developing brain. Common polymorphisms in
TCF4
and disruptive variants in the proximal region of the gene ...have been linked to relatively mild neuropsychiatric or neurodevelopmental disorders. In contrast, variants impacting distal exons are associated with Pitt–Hopkins syndrome (PTHS), a severe autosomal dominant condition characterized by profound intellectual disability, developmental delay, limited or absent speech, distinctive facies, and disordered breathing. Although phenotypic variability has been observed in PTHS, intellectual impairment and significant speech and motor delays are invariably present. In contrast to the typical de novo variants causing
TCF4
‐related disorder and PTHS, we report a familial form of
TCF4
‐related disorder where the missense variant arose de novo in the father and was inherited by two of his children. Although this family's variant's position in exon 18 predicted a typical PTHS phenotype, none of the affected individuals met the clinical diagnostic criteria for PTHS suggested by Zollino et al. in the first international consensus statement (as in the study by Zollino et al. in 2019). Rather, the three affected family members exhibited remarkably variable and milder phenotypes than would have been predicted from the position of their
TCF4
variant. Thus, the clinical spectrum of PTHS‐associated
TCF4
variants may be broader than previously reported.
This study used seven different adhesive removal systems to evaluate and compare enamel surface integrity, heat generation, and time consumed during residual cement removal after de-bracketing. The ...sample size was 140 human premolars. Teeth were cleaned, mounted, and prepared for orthodontic bracket bonding. Brackets were then debonded using bracket-removing pliers. Teeth were randomly assigned to seven groups based on the residual cement removal system: Group 1: Stainbuster bur, Group 2: Renew diamond bur #129, Group 3: Renew carbide bur, Group 4: OneGloss Complete system, Group 5: Sof-Lex system, Group 6: Enhance Finishing and PoGo Polishing complete kit, and Group 7: Renew friction grip points. The enamel surface was evaluated for roughness before bracketing and after residual cement removal using surface profilometry. The time taken for cement removal was recorded using a digital timer, and heat generation was measured using a laser thermometer before and after cement removal. One-way ANOVA compared the pre- and post-values for enamel surface roughness, temperature, and time consumed. When comparing the difference between the post- and pre-finishing roughness using one-way ANOVA, the Renew diamond bur produced the roughest enamel surface post-removal with a mean of 4.716 μm, while the Sof-Lex recorded the lowest at 0.760 μm. The highest mean temperature was recorded with the Stainbuster bur at 5.545 °C, and the lowest temperature was recorded with the Enhance bur at 2.260 °C. The time for cement removal was the shortest with the Enhance bur at 12.2 s, whereas the time was the longest with the Renew diamond bur at 30.4 s. In conclusion, all the residual cement removal systems used in this clinically simulated study were not able to restore the original enamel surface smoothness. However, the 3M Sof-Lex produced the lowest enamel roughness but with more time consumption and heat generation. When selecting the best residual cement removal system to be used, clinicians should weigh the merits and demerits of each system based on the clinical judgement of the operator.
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