<i>KIAA2022</i> nonsense mutation in a symptomatic female

Farach, Laura S.

doi:10.1002/ajmg.a.37479

Cited by 24 publications

(27 citation statements)

References 8 publications

(10 reference statements)

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“…The X-inactivation pattern was 65:35. Farach and Northrup11 reported a 17-year-old girl with a recurrent de novo non-sense mutation of KIAA2022 previously reported in a male (p.Arg322*) and a phenotype comparable to previously reported male patients, with severe ID, hypotonia, behavioural problems, microcephaly, growth retardation, mild dysmorphisms and seizures. An X-inactivation pattern of 73:27 was reported.…”

Section: Discussionsupporting

confidence: 77%

“…So far, the degree of KIAA2022 loss thus seems to correlate with the severity of the phenotype, with complete loss of expression predicting a severe phenotype. The patient reported by Farach and Northrup11 had a borderline skewed X-inactivation (73:27) and was also severely affected. In six out of seven tested female patients, a random XCI was found, and expression of KIAA2022 was on average two to three times lower than that in female controls, although this was not statistically significant.…”

Section: Discussionmentioning

confidence: 90%

“…All mutations were absent from the Exome Aggregation Consortium (ExAC) database (URL: http://exac.broadinstitute.org) (accessed October 2015) 17. All sequence alterations are in the large exon 3 (coding exon 2) and are predicted to activate non-sense mediated decay (NMD), with one recurrent mutation, p.Arg322*, that is present in one of the currently described females (patient 4), one male patient3 and one previously reported female 11. Overall, there seems to be no particular domain in which mutations cluster, consistent with the hypothesis that these truncating.…”

Section: Resultsmentioning

confidence: 99%

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De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

et al. 2016

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BackgroundMutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy.MethodsReported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible.ResultsAll mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles.ConclusionsHeterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

et al. 2016

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“…KIAA2022 is an X‐linked gene that has been implicated in X‐linked intellectual disability (XLID) (Athanasakis et al, ; Cantagrel et al, ; de Lange et al, ; Farach & Northrup, ; Kuroda et al, ; Moysés‐Oliveira et al, ; Van Maldergem et al, ; Webster et al, ). Pathogenic variants in X chromosome genes are believed to account for 5–10% of intellectual disabilities (ID) in males, and to date over 100 XLID genes have been discovered (Lubs, Stevenson, & Schwartz, ).…”

Section: Introductionmentioning

confidence: 99%

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature

Lorenzo

Stolte‐Dijkstra

Rheenen

et al. 2018

American J of Med Genetics Pt A

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KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together.

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“…males with severe to profound intellectual disabilities, autism, absent language development, and dysmorphic facial features. Since then, 16 more patients from nine families have been described with loss-of-function mutations in KIAA2022 and similar clinical phenotypes (8)(9)(10)(11)(12)(13). Females with de novo loss of function mutations in KIAA2022 have also recently been reported to be associated with intellectual disabilities and intractable epilepsy (14).…”

mentioning

confidence: 99%

De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females

Webster

Cho²,

Retterer³

et al. 2016

Clinical Genetics

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Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

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KIAA2022 nonsense mutation in a symptomatic female

Cited by 24 publications

References 8 publications

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature

De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females

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