Compound heterozygous microdeletion of chromosome 15q13.3 region in a child with hypotonia, impaired vision, and global developmental delay

Abstract Background: Adaptor protein complex-4 (AP-4), a heterotetrameric protein complex, plays an important role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with spastic tetraplegia, developmental delay and intellectual disability (ID).Case presentation: We report on a Chinese patient with infantile spasms, infantile hypotonia and global developmental delay. Exome sequencing showed compound heterozygous mutations in AP4M1(c.19A>G, p.I7V and c.137C>T, p.P46L).Conclusions: This is the first case of biallelic missense variants lay on the region encoding LH domain, which is important for membrane trafficking via protein–protein and intramolecular binding specificities. Our study expands the molecular spectrum associated with AP-4 deficiency syndrome, and reviews the clinical features of reported patients with AP4M1 mutations.

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Case Report: A Novel Compound Heterozygous Mutation of the FRMD4A Gene Identified in a Chinese Family With Global Developmental Delay, Intellectual Disability, and Ataxia

Frontiers in Pediatrics ◽

10.3389/fped.2021.775488 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuhua Pan ◽

Xiaoling Guo ◽

Xiaoqiang Zhou ◽

Yue Liu ◽

Jingli Lian ◽

...

Keyword(s):

Developmental Delay ◽

Intellectual Development ◽

Scaffolding Protein ◽

Compound Heterozygous Mutation ◽

Global Developmental Delay ◽

Chinese Family ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Missense Mutations ◽

Sequencing Data

Background: FERM domain-containing protein 4A (FRMD4A) is a scaffolding protein previously proposed to be critical in the regulation of cell polarity in neurons and implicated in human intellectual development.Case Presentation: We report a case of a 3-year-old boy with corpus callosum anomaly, relative macrocephaly, ataxia, and unexplained global developmental delay. Here, compound heterozygous missense mutations in the FRMD4A gene [c.1830G>A, p.(Met610Ile) and c.2973G>C, p.(Gln991His)] were identified in the proband, and subsequent familial segregation showed that each parent had transmitted a mutation.Conclusions: Our results have confirmed the associations of mutations in the FRMD4A gene with intellectual development and indicated that for patients with unexplained global developmental delay, the FRMD4A gene should be included in the analysis of whole exome sequencing data, which can contribute to the identification of more patients affected by this severe phenotypic spectrum.

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Identification of rare-disease genes in diverse undiagnosed cases using whole blood transcriptome sequencing and large control cohorts

10.1101/408492 ◽

2018 ◽

Cited By ~ 5

Author(s):

Laure Frésard ◽

Craig Smail ◽

Kevin S. Smith ◽

Nicole M. Ferraro ◽

Nicole A. Teran ◽

...

Keyword(s):

Rare Disease ◽

Developmental Delay ◽

Whole Blood ◽

Disease Diagnosis ◽

Global Developmental Delay ◽

Disease Genes ◽

Compound Heterozygous ◽

Mendelian Disease ◽

Rna Seq ◽

Pathogenic Variants

AbstractRNA sequencing (RNA-seq) is a complementary approach for Mendelian disease diagnosis for patients in whom exome-sequencing is not informative. For both rare neuromuscular and mitochondrial disorders, its application has improved diagnostic rates. However, the generalizability of this approach to diverse Mendelian diseases has yet to be evaluated. We sequenced whole blood RNA from 56 cases with undiagnosed rare diseases spanning 11 diverse disease categories to evaluate the general application of RNA-seq to Mendelian disease diagnosis. We developed a robust approach to compare rare disease cases to existing large sets of RNA-seq controls (N=1,594 external and N=31 family-based controls) and demonstrated the substantial impacts of gene and variant filtering strategies on disease gene identification when combined with RNA-seq. Across our cohort, we observed that RNA-seq yields a 8.5% diagnostic rate. These diagnoses included diseases where blood would not intuitively reflect evidence of disease. We identified RARS2 as an under-expression outlier containing compound heterozygous pathogenic variants for an individual exhibiting profound global developmental delay, seizures, microcephaly, hypotonia, and progressive scoliosis. We also identified a new splicing junction in KCTD7 for an individual with global developmental delay, loss of milestones, tremors and seizures. Our study provides a broad evaluation of blood RNA-seq for the diagnosis of rare disease.

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