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Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-beta signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-beta signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-beta signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome., Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930068, 81772299, 81822030, 82072391, 81972132, 81672123, 81972037, 81902178]; Beijing Natural Science FoundationBeijing Natural Science Foundation [JQ20032, 7191007]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-051, 2021-I2M-1-052]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320025]; Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program; PUMC Youth Fund & the Fundamental Research Funds for the Central Universities [3332019021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [K2015-54X-22 736-01-4, 2015-02227, 2018-03046]; Swedish Governmental Agency for Innovation Systems (Vinnova)Vinnova [2014-01438]; Marianne and Marcus Wallenberg Foundation; IngaBritt och Arne Lundbergs forskningsstiftelse; Byggmastare Olle Engkvist Stiftelse; Promobilia; Nyckelfonden; Stiftelsen Frimurare Barnhuset i Stockholm; Region Stockholm; Karolinska Institutet, Stockholm, Sweden; orebro University, orebro, Sweden; Sallskapet Barnavard; Karolinska InstitutetKarolinska Institutet; Stiftelsen Sallsyntafonden; Stiftelsen Samariten; Stiftelsen Promobilia; Region Stockholm [20180131, 20200500]; US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke [NINDS R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; US NIH National Human Genome Research Institute [NHGRI K08 HG008986]

Objective: Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms. Material and methods: Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene. Results: Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their childs psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms. Conclusions: While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an, Funding Agencies|Horselskadades Riksforbund (National Association of Hearing Impairment); ALF ( Stockholm County Council)Stockholm County Council; ALF (Karolinska Institute); ALF (Karolinska Hospital)

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-beta signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-beta signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-beta signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome., Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930068, 81772299, 81822030, 82072391, 81972132, 81672123, 81972037, 81902178]; Beijing Natural Science FoundationBeijing Natural Science Foundation [JQ20032, 7191007]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-051, 2021-I2M-1-052]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320025]; Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program; PUMC Youth Fund & the Fundamental Research Funds for the Central Universities [3332019021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [K2015-54X-22 736-01-4, 2015-02227, 2018-03046]; Swedish Governmental Agency for Innovation Systems (Vinnova)Vinnova [2014-01438]; Marianne and Marcus Wallenberg Foundation; IngaBritt och Arne Lundbergs forskningsstiftelse; Byggmastare Olle Engkvist Stiftelse; Promobilia; Nyckelfonden; Stiftelsen Frimurare Barnhuset i Stockholm; Region Stockholm; Karolinska Institutet, Stockholm, Sweden; orebro University, orebro, Sweden; Sallskapet Barnavard; Karolinska InstitutetKarolinska Institutet; Stiftelsen Sallsyntafonden; Stiftelsen Samariten; Stiftelsen Promobilia; Region Stockholm [20180131, 20200500]; US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke [NINDS R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; US NIH National Human Genome Research Institute [NHGRI K08 HG008986]

Objective: Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms. Material and methods: Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene. Results: Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their childs psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms. Conclusions: While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an, Funding Agencies|Horselskadades Riksforbund (National Association of Hearing Impairment); ALF ( Stockholm County Council)Stockholm County Council; ALF (Karolinska Institute); ALF (Karolinska Hospital)

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-beta signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-beta signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-beta signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome., Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930068, 81772299, 81822030, 82072391, 81972132, 81672123, 81972037, 81902178]; Beijing Natural Science FoundationBeijing Natural Science Foundation [JQ20032, 7191007]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-051, 2021-I2M-1-052]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320025]; Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program; PUMC Youth Fund & the Fundamental Research Funds for the Central Universities [3332019021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [K2015-54X-22 736-01-4, 2015-02227, 2018-03046]; Swedish Governmental Agency for Innovation Systems (Vinnova)Vinnova [2014-01438]; Marianne and Marcus Wallenberg Foundation; IngaBritt och Arne Lundbergs forskningsstiftelse; Byggmastare Olle Engkvist Stiftelse; Promobilia; Nyckelfonden; Stiftelsen Frimurare Barnhuset i Stockholm; Region Stockholm; Karolinska Institutet, Stockholm, Sweden; orebro University, orebro, Sweden; Sallskapet Barnavard; Karolinska InstitutetKarolinska Institutet; Stiftelsen Sallsyntafonden; Stiftelsen Samariten; Stiftelsen Promobilia; Region Stockholm [20180131, 20200500]; US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke [NINDS R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; US NIH National Human Genome Research Institute [NHGRI K08 HG008986]

Objective: Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms. Material and methods: Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene. Results: Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their childs psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms. Conclusions: While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an, Funding Agencies|Horselskadades Riksforbund (National Association of Hearing Impairment); ALF ( Stockholm County Council)Stockholm County Council; ALF (Karolinska Institute); ALF (Karolinska Hospital)

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-beta signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-beta signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-beta signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome., Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930068, 81772299, 81822030, 82072391, 81972132, 81672123, 81972037, 81902178]; Beijing Natural Science FoundationBeijing Natural Science Foundation [JQ20032, 7191007]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-051, 2021-I2M-1-052]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320025]; Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program; PUMC Youth Fund & the Fundamental Research Funds for the Central Universities [3332019021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [K2015-54X-22 736-01-4, 2015-02227, 2018-03046]; Swedish Governmental Agency for Innovation Systems (Vinnova)Vinnova [2014-01438]; Marianne and Marcus Wallenberg Foundation; IngaBritt och Arne Lundbergs forskningsstiftelse; Byggmastare Olle Engkvist Stiftelse; Promobilia; Nyckelfonden; Stiftelsen Frimurare Barnhuset i Stockholm; Region Stockholm; Karolinska Institutet, Stockholm, Sweden; orebro University, orebro, Sweden; Sallskapet Barnavard; Karolinska InstitutetKarolinska Institutet; Stiftelsen Sallsyntafonden; Stiftelsen Samariten; Stiftelsen Promobilia; Region Stockholm [20180131, 20200500]; US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke [NINDS R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; US NIH National Human Genome Research Institute [NHGRI K08 HG008986]

Objective: Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms. Material and methods: Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene. Results: Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their childs psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms. Conclusions: While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an, Funding Agencies|Horselskadades Riksforbund (National Association of Hearing Impairment); ALF ( Stockholm County Council)Stockholm County Council; ALF (Karolinska Institute); ALF (Karolinska Hospital)

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-beta signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-beta signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-beta signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome., Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930068, 81772299, 81822030, 82072391, 81972132, 81672123, 81972037, 81902178]; Beijing Natural Science FoundationBeijing Natural Science Foundation [JQ20032, 7191007]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-051, 2021-I2M-1-052]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320025]; Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program; PUMC Youth Fund & the Fundamental Research Funds for the Central Universities [3332019021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [K2015-54X-22 736-01-4, 2015-02227, 2018-03046]; Swedish Governmental Agency for Innovation Systems (Vinnova)Vinnova [2014-01438]; Marianne and Marcus Wallenberg Foundation; IngaBritt och Arne Lundbergs forskningsstiftelse; Byggmastare Olle Engkvist Stiftelse; Promobilia; Nyckelfonden; Stiftelsen Frimurare Barnhuset i Stockholm; Region Stockholm; Karolinska Institutet, Stockholm, Sweden; orebro University, orebro, Sweden; Sallskapet Barnavard; Karolinska InstitutetKarolinska Institutet; Stiftelsen Sallsyntafonden; Stiftelsen Samariten; Stiftelsen Promobilia; Region Stockholm [20180131, 20200500]; US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke [NINDS R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; US NIH National Human Genome Research Institute [NHGRI K08 HG008986]

Objective: Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms. Material and methods: Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene. Results: Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their childs psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms. Conclusions: While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an, Funding Agencies|Horselskadades Riksforbund (National Association of Hearing Impairment); ALF ( Stockholm County Council)Stockholm County Council; ALF (Karolinska Institute); ALF (Karolinska Hospital)