Expanding the Phenotype of the FAM149B1-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family

Biallelic truncating FAM149B1 variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known FAM1...

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Autores principales:	Sandy Siegert, Gabriel T. Mindler, Christof Brücke, Andreas Kranzl, Janina Patsch, Markus Ritter, Andreas R. Janecke, Julia Vodopiutz
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>KMT2B</i> <i>POLG2</i> <i>FAM149B1</i> ciliopathy duane syndrome precision medicine Genetics QH426-470
Acceso en línea:	https://doaj.org/article/455b181e07fb4e8aa99e18ee1bbd1fc7
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spelling	oai:doaj.org-article:455b181e07fb4e8aa99e18ee1bbd1fc72021-11-25T17:40:10ZExpanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family10.3390/genes121116482073-4425https://doaj.org/article/455b181e07fb4e8aa99e18ee1bbd1fc72021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1648https://doaj.org/toc/2073-4425Biallelic truncating <i>FAM149B1</i> variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known <i>FAM149B1</i> c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in <i>FAM149B1</i>-ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the <i>FAM149B1</i>-related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of <i>FAM149B1</i>-related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.Sandy SiegertGabriel T. MindlerChristof BrückeAndreas KranzlJanina PatschMarkus RitterAndreas R. JaneckeJulia VodopiutzMDPI AGarticle<i>KMT2B</i><i>POLG2</i><i>FAM149B1</i>ciliopathyduane syndromeprecision medicineGeneticsQH426-470ENGenes, Vol 12, Iss 1648, p 1648 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>KMT2B</i> <i>POLG2</i> <i>FAM149B1</i> ciliopathy duane syndrome precision medicine Genetics QH426-470
spellingShingle	<i>KMT2B</i> <i>POLG2</i> <i>FAM149B1</i> ciliopathy duane syndrome precision medicine Genetics QH426-470 Sandy Siegert Gabriel T. Mindler Christof Brücke Andreas Kranzl Janina Patsch Markus Ritter Andreas R. Janecke Julia Vodopiutz Expanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family
description	Biallelic truncating <i>FAM149B1</i> variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known <i>FAM149B1</i> c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in <i>FAM149B1</i>-ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the <i>FAM149B1</i>-related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of <i>FAM149B1</i>-related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.
format	article
author	Sandy Siegert Gabriel T. Mindler Christof Brücke Andreas Kranzl Janina Patsch Markus Ritter Andreas R. Janecke Julia Vodopiutz
author_facet	Sandy Siegert Gabriel T. Mindler Christof Brücke Andreas Kranzl Janina Patsch Markus Ritter Andreas R. Janecke Julia Vodopiutz
author_sort	Sandy Siegert
title	Expanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family
title_short	Expanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family
title_full	Expanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family
title_fullStr	Expanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family
title_full_unstemmed	Expanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family
title_sort	expanding the phenotype of the <i>fam149b1</i>-related ciliopathy and identification of three neurogenetic disorders in a single family
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/455b181e07fb4e8aa99e18ee1bbd1fc7
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Expanding the Phenotype of the <i>FAM149B1</i>-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family

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