X‐linked intellectual disability: Unique vulnerability of the male genome

Stevenson, Roger E.; Schwartz, Charles E.

doi:10.1002/ddrr.81

Cited by 58 publications

(33 citation statements)

References 41 publications

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“…44,45 Part of this distortion of the gender ratio is attributable to X-linked genetic disorders. 46 Consequently, genetic testing for X-linked genes in boys with GDD/ID is often warranted, particularly in patients whose pedigree is suggestive of an X-linked condition. In addition, for several reasons, research in X-linked genes that cause ID is advanced over autosomal genes, 46,47 thus accelerating the clinical capacity to diagnose XLID over autosomal forms.…”

Section: Male Gendermentioning

confidence: 99%

“…46 Fragile X testing should be performed in all boys and girls with GDD/ID of unknown cause. Of boys with GDD/ID of uncertain cause, 2% to 3% will have fragile X syndrome (full mutation of FMR1, >200 CGG repeats), as will 1% to 2% of girls (full mutation).…”

Section: Male Gendermentioning

confidence: 99%

“…50 In excess of 215 XLID conditions have been recorded, and >90 XLID genes have been identified. 46,50 To address male patients with GDD/ID and X-linked inheritance, there are molecular genetic diagnostic "panels" of X-linked genes available clinically. These panels examine many genes in 1 "test sample.…”

Section: Genetic Testing For Nonspecific Xlidmentioning

confidence: 99%

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Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

Moeschler¹,

Shevell²,

Saul³

et al. 2014

Pediatrics

461

421

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Global developmental delay and intellectual disability are relatively common pediatric conditions. This report describes the recommended clinical genetics diagnostic approach. The report is based on a review of published reports, most consisting of medium to large case series of diagnostic tests used, and the proportion of those that led to a diagnosis in such patients. Chromosome microarray is designated as a first-line test and replaces the standard karyotype and fluorescent in situ hybridization subtelomere tests for the child with intellectual disability of unknown etiology. Fragile X testing remains an important first-line test. The importance of considering testing for inborn errors of metabolism in this population is supported by a recent systematic review of the literature and several case series recently published. The role of brain MRI remains important in certain patients. There is also a discussion of the emerging literature on the use of whole-exome sequencing as a diagnostic test in this population. Finally, the importance of intentional comanagement among families, the medical home, and the clinical genetics specialty clinic is discussed.

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Section: Male Gendermentioning

confidence: 99%

Section: Male Gendermentioning

confidence: 99%

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Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

Moeschler¹,

Shevell²,

Saul³

et al. 2014

Pediatrics

461

421

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“…Indeed, more than 102 genes have been involved in syndromic form of XLID, making molecular diagnosis and thus genetic counselling difficult. [2][3][4] Among XLID, syndromic and nonsyndromic forms are delineated based on observed additional features that are associated with ID such as seizures, abnormal growth parameters, visceral or cerebral malformation, and so on. Recently, mutations in IQSEC2 (Sec7 domain of, and IQ-like domain) have been shown to cause nonsyndromic XLID with behavioural disturbance.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability

et al. 2013

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Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C. Keywords: syndromic X-linked intellectual disability; microcephaly; IQSEC2-truncating mutations INTRODUCTIONIntellectual disability (ID) is defined by substantial limitations in cognitive functioning (intellectual quotient o70) coupled with a deficit in adaptive behaviour and onset before the age of 18 years. ID is frequent in the general population, with as many as 1 in every 50 individuals directly affected worldwide. 1,2 Among the genetic etiologies of ID, XLID is a frequent cause, estimated at 5-10% of all cases in males, with a major genetic heterogeneity. Indeed, more than 102 genes have been involved in syndromic form of XLID, making molecular diagnosis and thus genetic counselling difficult. 2-4 Among XLID, syndromic and nonsyndromic forms are delineated based on observed additional features that are associated with ID such as seizures, abnormal growth parameters, visceral or cerebral malformation, and so on. Recently, mutations in IQSEC2 (Sec7 domain of, and IQ-like domain) have been shown to cause nonsyndromic XLID with behavioural disturbance. 5-8 We report on three male patients with severe syndromic XLID and truncating mutations in IQSEC2. PATIENTS AND METHODS Patient 1This patient was referred to the Genetics Department for severe ID and postnatal microcephaly. He is the only child born to healthy unrelated parents native to the south of France. Pregnancy was uneventful. The boy was born at 37 ½ weeks of gestation full term by caesarean section due to an abnormal presentation. Birth measurements were in the normal range (occipital frontal circumference (OFC) 36 cm, þ 1 SD; birth weight 3430 g, mean; birth length 52.5 cm, þ 1 SD). Postnatal course was marked by psychomotor retardation with neonatal hypotonia, hyperkinesia, strabismus and non-inherited progressive postnatal microcephaly with OFC at À2 SD at 6 months of age. He sat at 12 months and did not vocalize at 15 months. At the time of the last evaluation, he was 4 years old. He presented with normal facial features ( Figure 1a). OFC was at 48 cm, À2.5 SD; weight at 2 kg, þ 2 SD and length at 106 cm, þ 1 SD. Language was not acquired and he could not walk alone. He h...

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“…1, а). Экспансия тринуклеотидных повторов была обнару-жена в 46 (40%) из 114 случаев, что в более чем 10 раз превышает процент подтверждения этого диагноза в зарубежных генетических центрах (2-3,8%) [8]. По-лученные данные указывают на эффективность отбо-ра больных с помощью количественной клинической шкалы.…”

Section: генеалогические исследования в семьях с х-сцепленной умственunclassified

An algorithm for the diagnosis of X-linked intellectual disability in children

Воинова¹,

Ворсанова²,

Юров³

et al. 2016

Ross. vestn. perinatol. pediatr.

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X‐linked intellectual disability: Unique vulnerability of the male genome

Cited by 58 publications

References 41 publications

Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability

An algorithm for the diagnosis of X-linked intellectual disability in children

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