Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5

Abstract

Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine. Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation. Here, a Pakistani family with parental consanguinity was presented, characterized with severe intellectual disability (ID), spastic paraplegia, and deafness. Homozygosity mapping, integrated single nucleotide polymorphism (SNP) array, whole-exome sequencing, and whole-genome sequencing were performed, and homozygous variants in TMEM141 (c.270G>A, p.Trp90*), DDHD2 (c.411+767_c.1249-327del), and LHFPL5 (c.250delC, p.Leu84*) were identified. A Tmem141^{p.Trp90*/p.Trp90*} mouse model was generated. Behavioral studies showed impairments in learning ability and motor coordination. Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells. Transmission electron microscopy showed abnormal mitochondrial morphology. Furthermore, studies on a human in vitro neuronal model (SH-SY5Y cells) with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function, possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model. Conclusively, panoramic variation analysis revealed that multilocus genomic variations of TMEM141, DDHD2, and LHFPL5 together caused variable phenotypes in patient. Notably, the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

Keywords

neurodevelopmental disorder / autosomal recessive intellectual disability / consanguinity / spastic paraplegia / hearing loss / TMEM141

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Acknowledgements

We would like to thank all the individuals for their collaboration. This work was financially supported by the National Natural Science Foundation of China (NSFC) (Nos. 82001221 and 81788101), the National Key Research and Development Program of China (Nos. 2022YFC2703900 and 2022YFC2703903), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (Nos. 2021-I2M-1-018, 2022-I2M-JB-004 and 2017-I2M-B&R-05).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1006-x and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Liwei Sun, Xueting Yang, Amjad Khan, Xue Yu, Han Zhang, Shirui Han, Xiaerbati Habulieti, Yang Sun, Rongrong Wang, and Xue Zhang declare that they have no conflict of interest.

The study was approved by Peking Union Medical College Institutional Review Board and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from the patient and her family members. All institutional and national guidelines for the care and use of laboratory animals were followed.

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