Functional validation of novel variants in B4GALNT1 associated with early‐onset complex hereditary spastic paraplegia with impaired ganglioside synthesis

Childhood‐onset forms of hereditary spastic paraplegia are ultra‐rare diseases and often present with complex features. Next‐generation‐sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where s...

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Published in:	American journal of medical genetics. Part A Vol. 188; no. 9; pp. 2590 - 2598
Main Authors:	Alecu, Julian Emanuel, Ohmi, Yuhsuke, Bhuiyan, Robiul H., Inamori, Kei‐ichiro, Nitta, Takahiro, Saffari, Afshin, Jumo, Hellen, Ziegler, Marvin, Gusmao, Claudio Melo, Sharma, Nutan, Ohno, Shiho, Manabe, Noriyoshi, Yamaguchi, Yoshiki, Kambe, Mariko, Furukawa, Keiko, Sahin, Mustafa, Inokuchi, Jin‐ichi, Furakawa, Koichi, Ebrahimi‐Fakhari, Darius
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-09-2022 Wiley Subscription Services, Inc
Subjects:	Adolescent Cell culture Child Children Diagnosis Female Fibroblasts Gait Gangliosides Gangliosides - genetics Hereditary spastic paraplegia Humans inborn error of metabolism Intellectual disabilities Missense mutation Mutation neurodegeneration Paralysis Patients Pedigree Phenotyping Rare Diseases Reflexes spastic paraplegia 26 Spastic Paraplegia, Hereditary - diagnosis Spastic Paraplegia, Hereditary - genetics Spasticity gangliosides neurodegeneration spastic paraplegia 26 spasticity inborn error of metabolism hereditary spastic paraplegia
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Summary:	Childhood‐onset forms of hereditary spastic paraplegia are ultra‐rare diseases and often present with complex features. Next‐generation‐sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient‐derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13‐year‐old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic‐ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice‐site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532‐1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient‐derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1‐associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra‐rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.
Bibliography:	Funding information Julian Emanuel Alecu, Yuhsuke Ohmi, Robiul H. Bhuiyan, and Kei‐ichiro Inamori contributed equally to this study. Jin‐ichi Inokuchi, Koichi Furakawa, and Darius Ebrahimi‐Fakhari contributed equally to this study. CureAP4 Foundation; CureSPG50 Foundation; Deutsche Forschungsgemeinschaft, Grant/Award Numbers: 270949263/GRK2162, SA 4171/1‐1; Deutscher Akademischer Austauschdienst; Japan Agency for Medical Research and Development; Japan Science and Technology Corporation; Japan Society for the Promotion of Science, Grant/Award Numbers: 19K22518, 19K07393, 1K06828, 1H02699, 20H03452, JP21K06531; Manton Center for Orphan Disease Research, Boston Children's Hospital; Max Weber‐Program of the State of Bavaria; Ministry of Education, Culture, Sports, Science and Technology; National Institute of Neurological Disorders and Stroke, Grant/Award Number: 1K08NS123552‐01; Spastic Paraplegia Foundation; Studienstiftung des Deutschen Volkes; Takeda Science Foundation; JST‐CREST, Grant/Award Number: JPMJCR17H2; German Academic Exchange Service (DAAD); German National Academic Foundation ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 Contributed equally
ISSN:	1552-4825 1552-4833
DOI:	10.1002/ajmg.a.62880