Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome

Shaw, Marie; Yap, Tzu Ying; Henden, Lyndal; Bahlo, Melanie; Gardner, Alison; Kalscheuer, Vera M.; Haan, Eric; Christie, Louise; Hackett, Anna; Gécz, Jozef

doi:10.1016/j.ejmg.2015.04.004

Cited by 18 publications

(14 citation statements)

References 14 publications

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“…1) as described by Hu et al (11). Subsequent whole-genome sequencing and alignment was performed on IV:6 and VI:1 as previously described (126). Using genomic DNA from the proband and parents, the exonic regions and flanking splice junctions of the genome were captured using the Clinical Research Exome kit (Agilent Technologies, Santa Clara, CA).…”

Section: Dna Sequencing and Alignmentmentioning

confidence: 99%

A recurrent missense variant inSLC9A7causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation

Khayat

Hackett

Shaw

et al. 2018

Human Molecular Genetics

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We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles. In transfected Chinese hamster ovary AP-1 cells, the Leu515Phe mutant protein was correctly targeted to the TGN/post-Golgi vesicles, but its N-linked oligosaccharide maturation as well as that of a co-transfected secretory membrane glycoprotein, vesicular stomatitis virus G (VSVG) glycoprotein, was reduced compared to cells co-expressing SLC9A7 wild-type and VSVG. This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function. Membrane trafficking of glycosylation-deficient Leu515Phe and co-transfected VSVG to the cell surface, however, was relatively unaffected. Mass spectrometry analysis of patient sera also revealed an abnormal

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Section: Dna Sequencing and Alignmentmentioning

confidence: 99%

A recurrent missense variant inSLC9A7causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation

Khayat

Hackett

Shaw

et al. 2018

Human Molecular Genetics

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“…In practice, long tracts of IBD (>3 cM) can be accurately detected using genetic data between individuals with a common ancestor from the past 4–50 generations ( Browning and Browning, 2012 ). Detection of IBD haplotypes can allow for the identification of distantly related patients with a genetic disorder driven by a locus inherited from a founding ancestor who brought the disease mutation into a population ( Houwen et al, 1994 ; Kenny et al, 2009 ; Henden et al, 2016 ; Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC) et al, 2010 ; Traherne et al, 2016 ; Shaw et al, 2015 ; Ko et al, 2014 ; Lalli et al, 2014 ). This is the principle underlying population-scale disease mapping approaches that combine IBD sharing and statistical association to discover novel disease loci, so called IBD-mapping.…”

Section: Introductionmentioning

confidence: 99%

Genetic identification of a common collagen disease in Puerto Ricans via identity-by-descent mapping in a health system

Belbin

Odgis

Sorokin

et al. 2017

eLife

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Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.

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“…We also found that (rs28933690) (C294R) pathogenic, which is matched with the clinical result that we retrieved from dbSNPs/NCBI database .also we Retrieved (rs145996031) (Y370D) as untested we found to be damaging. Interestingly we found that, (rs145996031) (Y370D) novel SNP may also cause L1 syndrome (53).…”

Section: Discussionmentioning

confidence: 72%

Unmasking of novel mutations within XK gene that could be used as Diagnostic Markers to Predict McLeod syndrome: Using in silico analysis

Mustafa

Ma²

2019

Preprint

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Background:McLeod neuroacanthocytosis syndrome is a rare X-linked recessive multisystem disorder affecting the peripheral and central nervous systems, red blood cells, and internal organs. Methods:We carried out in silico analysis of structural effect of each SNP using different bioinformatics tools to predict substitution influence on protein structural and functional level. Result: 2 novel mutations out of 104 nsSNPs that are found to be deleterious effect on the XK structure and function. Conclusion: The present study provided a novel insight into the understanding of McLeod syndrome, SNPs occurring in coding and non-coding regions, may lead to RNA alterations and should be systematically verified. Functional studies can gain from a preliminary multi-step approach, such as the one proposed here; we prioritize SNPs for further genetic mapping studies. This will be a valuable resource for neurologists, hematologists, and clinical geneticists on this rare and debilitating disease.

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Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome

Cited by 18 publications

References 14 publications

A recurrent missense variant inSLC9A7causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation

A recurrent missense variant inSLC9A7causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation

Genetic identification of a common collagen disease in Puerto Ricans via identity-by-descent mapping in a health system

Unmasking of novel mutations within XK gene that could be used as Diagnostic Markers to Predict McLeod syndrome: Using in silico analysis

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