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Growth and neurodevelopmental disorder with arthrogryposis, microcephaly and structural brain anomalies caused by Bi-allelic partial deletion of SMPD4 gene

Abstract

Neutral sphingomyelinases have an important role in generation of ceramide and phosphorylcholine from sphingomyelins which then act as secondary messengers in various signaling pathways of the cellular machinery. They function ubiquitously with a predominant role in the central nervous system. Neutral sphingomyelinase type 3, encoded by SMPD4 gene has recently been reported to cause a severe autosomal recessive neurodevelopmental disorder with congenital arthrogryposis and microcephaly. We report a 22-month-old girl having characteristic features of neurodevelopmental delay, prenatal onset growth failure, arthrogryposis, microcephaly and brain anomalies including severe hypomyelination, simplified gyral pattern and hypoplasia of corpus callosum and brain stem. In addition, she was noted to have nystagmus and visual impairment secondary to macular dystrophy and retinal pigment epithelial stippling at posterior pole. Copy number variant analysis from trio whole exome sequencing (ES) enabled identification of a homozygous 11 kb deletion encompassing exons 18–20 of SMPD 4 gene, confirming the diagnosis of SMPD4-related disorder in her.

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Fig. 1: Pictorial details of the patient shown in pedigree, clinical photographs, MRI images and genetic test results.

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The data pertaining to this work will be made available upon a reasonable request to the corresponding author.

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Acknowledgements

We thank the proband and her family for participating in this study. A part of this work was funded by National Institutes of Health, USA under the project titled ‘Genetic Diagnosis of Neurodevelopmental Disorders in India’ Grant ID - R01 HD093570 01 A1 (PI). The trio-WES was funded by Medgenome Laboratories Ltd. The authors also acknowledge the contributions from Dr Renu Saxena, head of Molecular Genetics laboratory and Dr I C Verma and Dr Ratna D Puri, senior clinical geneticists at Sir Ganga Ram Hospital, for significant intellectual discussions.

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Clinical evaluation and paper writing and revision: SB-M; Neuroimaging evaluation-SS; Bioinformatic data processing and analysis-SK; whole exome sequencing-VLR and SM; Exome analysis, variant interpretation, and paper writing-PK; quantitative PCR, result interpretation and paper writing-PHS; Supervision, funding acquisition and revision of paper-AS.

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Correspondence to Sunita Bijarnia-Mahay or Anju Shukla.

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Bijarnia-Mahay, S., Somashekar, P.H., Kaur, P. et al. Growth and neurodevelopmental disorder with arthrogryposis, microcephaly and structural brain anomalies caused by Bi-allelic partial deletion of SMPD4 gene. J Hum Genet 67, 133–136 (2022). https://doi.org/10.1038/s10038-021-00981-3

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