Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing

Schuurs-Hoeijmakers, Janneke; Silfhout, Anneke T. Vulto-van; Vissers, Lisenka E.L.M.; Vondervoort, Ilse I.G.M. van de; Bon, Bregje W.M. van; Ligt, Joep de; Gilissen, Christian; Hehir-Kwa, Jayne Y.; Neveling, Kornelia; Rosario, Marisol del; Hira, Gausiya; Reitano, S; Vitello, Girolamo Aurelio; Failla, Pinella; Greco, Donatella; Fichera, Marco; Galesi, Ornella; Kleefstra, Tjitske; Greally, Marie T.; Ockeloen, Charlotte W.; Willemsen, Marjolein H.; Bongers, Ernie M.H.F.; Janssen, Irene M.; Pfundt, Rolph; Veltman, Joris A.; Romano, Corrado; Willemsen, M.A.A.P.; Bokhoven, Hans van; Brunner, Han G.; Vries, Bert B.A. de; Brouwer, Arjan P.M. de

doi:10.1136/jmedgenet-2013-101644

Cited by 90 publications

(66 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similarly in a whole-exome sequencing project of multiplex, non-consanguineous pedigrees with ID, one in nineteen families exhibited a protein truncating mutation in NHE6 . 29 If we assume that between 1–3% of the world’s population is diagnosed with an intellectual disability, and approximately 10–20% of the causes are due to X-linked genes, then we can estimate that CS may affect between 1 in 16,000 to 100,000 people. By comparison, this represents approximately 10–50% the prevalence of Fragile X syndrome, the most commonly inherited form of intellectual disability.…”

Section: Discussionmentioning

confidence: 99%

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

Pescosolido

Stein

Schmidt

et al. 2014

Annals of Neurology

158

View full text Add to dashboard Cite

Objective Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na+/H+ Exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. Methods Twelve independent pedigrees (14 boys, ages 4 to 19) with mutations in NHE6 were administered standardized research assessments and mutations were characterized. Results The mutational spectrum was composed of 9 single nucleotide variants (SNVs), 2 indels and 1 CNV deletion. All mutations were protein-truncating or splicing mutations. We identified two recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, seven of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical and behavioral symptoms. All CS participants were non-verbal and had intellectual disability, epilepsy and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%) and MRI evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%) and a majority exhibited high pain threshold. Interpretation This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy and regression.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

Pescosolido

Stein

Schmidt

et al. 2014

Annals of Neurology

158

View full text Add to dashboard Cite

show abstract

“…Although Zhao et al 16 , found no obvious developmental abnormalities in homozygous PTPRT knockout mice, it is possible that it functions in certain genetic background or environmental conditions 17 . Combinations of a heterozygous missense mutation at the conserved PTP catalytic domain of PTPRT and a heterozygous intronic deletion of 150 kb removing more than half of intron 1 of PTPRT were reported in a Dutch family of three brothers and two sisters affected with intellectual disability, together with congenital cardiac defects 18 , indicating possible essential function of PTPRT in heart development. In addition, using European GW scan data, we found that rs490514 is also associated with the risk of CHD in Europeans, although the allele frequency of rs490514 in both populations was greatly different (Chinese population: MAF ¼ 0.39 in controls; European population: MAF ¼ 0.11 in controls).…”

Section: Discussionmentioning

confidence: 99%

Association analysis identifies new risk loci for congenital heart disease in Chinese populations

et al. 2015

View full text Add to dashboard Cite

Our previous genome-wide association study (GWAS) identified two susceptibility loci for congenital heart disease (CHD) in Han Chinese. Here we identify additional loci by testing promising associations in an extended 3-stage validation consisting of 6,053 CHD cases and 7,410 controls. We find GW significant (Po5.0 Â 10 À 8 ) evidence of 4 additional CHD susceptibility loci at 4q31.22 (rs1400558, upstream of EDNRA, P all ¼ 1.63 Â 10 À 9 ), 9p24.2 (rs7863990, close to SMARCA2, P all ¼ 3.71 Â 10 À 14 ), 12q24.13 (rs2433752, upstream of TBX3 and TBX5, P all ¼ 1.04 Â 10 À 10 ) and 20q12 (rs490514, in PTPRT, P all ¼ 1.20 Â 10 À 13 ). Moreover, the data from previous European GWAS supports that rs490514 is associated with the risk of CHD (P ¼ 3.40 Â 10 À 3 ). These results enhance our understanding of CHD susceptibility.

show abstract

“…A variety of inherited and de novo mutations in NHE6 have recently been identified in CS patients, including frameshifts, nonsense, missense and deletions, although their precise consequences on neuronal function have yet to be elucidated [2, 3, 8, 9, 11, 12, 32–41]. The majority of these mutations cause premature translation termination and loss-of-function.…”

Section: Introductionmentioning

confidence: 99%

A Christianson syndrome-linked deletion mutation (∆287ES288) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death

Ilie

Gao

Reid

et al. 2016

Mol Neurodegeneration

View full text Add to dashboard Cite

BackgroundChristianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail.MethodsHere, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu287 and Ser288 (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability.ResultsIn the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death.ConclusionsThese results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0129-9) contains supplementary material, which is available to authorized users.

show abstract

Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing

Abstract: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

Cited by 90 publications

References 40 publications

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

Association analysis identifies new risk loci for congenital heart disease in Chinese populations

A Christianson syndrome-linked deletion mutation (∆287ES288) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death

Contact Info

Product

Resources

About