A 10.46 Mb 12p11.1–12.1 interstitial deletion coincident with a 0.19 Mb NRXN1 deletion detected by array CGH in a girl with scoliosis and autism

Abstract

We present a 12-year-old girl with de novo karyotype 46,XX,del(12)(p11.1p12.1). Array CGH revealed in addition to a 10.466 Mb interstitial deletion on 12p11.1→12p12.1 a 0.191 Mb deletion on 2p16.3. The girl presented with mild facial dysmorphism consisting of microcephaly, hypertelorism, downslanting palpebral fissures, strabismus, broad nasal base, bulbous nose, short philtrum, micro/retrognathia, irregular tooth arrangement, phalangeal deformity in distal phalanges of hands, 5th finger camptodactyly, brachydactyly in feet, history of joint hypermobility, and scoliosis. She was considered to have mild to moderate mental retardation and ascertained for an autism spectrum disorder(ASD). Short arm of chromosome 12 interstitial deletions are rarely reported whereas point mutations and deletions of NRXN1, which is located on chromosome 2p16.3, are associated with ASDs. In this article we present and discuss the phenotypic consequences of a patient who was affected by deletions of two different chromosomal regions.

Exome sequencing expands the mechanism of SOX5‐associated intellectual disability: A case presentation with review of sox‐related disorders

“…There were 11 reported patients with cytogenetic abnormalities involving only SOX5 . These patients shared a phenotype of mild to severe developmental delay with more severely affected speech, dysmorphic features including down slanting palpebral fissures, frontal bossing, crowded teeth, auricular abnormalities, and prominent philtral ridges, hypotonia, strabismus, and behavioral abnormalities [Soysal et al, ; Lee et al, ; Schanze et al, ]. It became clear through multiple reports that haploinsufficiency of SOX5 was responsible for these features, yet no reports of patients with intragenic point mutations in the SOX5 gene have been published.…”

Investigation ofNRXN1deletions: Clinical and molecular characterization

“…Heterozygous partial deletions, as well as other mutations and disruptions, of NRXN1 have been reported in association with susceptibility for neurocognitive disabilities, such as autism spectrum disorders (ASDs) [Feng et al, 2006; Szatmari et al, 2007; Kim et al, 2008; Yan et al, 2008; Bucan et al, 2009; Glessner et al, 2009; Guilmatre et al, 2009; Gauthier et al, 2011; Sanders et al, 2011; Soysal et al, 2011; Duong et al, 2012; Gai et al, 2012; Hedges et al, 2012; Liu et al, 2012], intellectual disability (ID) [Friedman et al, 2006; Zahir et al, 2008; Guilmatre et al, 2009; Ching et al, 2010; Wisniowiecka‐Kowalnik et al, 2010; Gregor et al, 2011; Schaaf et al, 2012], and schizophrenia [Kirov et al, 2008; Vrijenhoek et al, 2008; Walsh et al, 2008; Guilmatre et al, 2009; Kirov et al, 2009; Need et al, 2009; Rujescu et al, 2009; Ikeda et al, 2010; Magri et al, 2010; Shah et al, 2010; Gauthier et al, 2011; Levinson et al, 2011; Muhleisen et al, 2011; Stewart et al, 2011; Duong et al, 2012] (Table I). Although multiple studies have shown a significantly higher frequency of NRXN1 defects in patient populations in comparison to control populations, NRXN1 alterations have also been identified in normal parents and healthy controls [Feng et al, 2006; Bucan et al, 2009; Kirov et al, 2009; Need et al, 2009; Rujescu et al, 2009; Zweier et al, 2009; Ching et al, 2010; Gregor et al, 2011; Levinson et al, 2011; Sanders et al, 2011; Gai et al, 2012; Hedges et al, 2012; Schaaf et al, 2012].…”

Molecular Analysis of a Deletion Hotspot in the NRXN1 Region Reveals the Involvement of Short Inverted Repeats in Deletion CNVs

“…This suggests that the disruption of NRXN1 is among the strongest ASD susceptibility candidates identified to date. [5][6][7][8][9][10][11][12][13][14] NRXN1 deletions have also been linked to schizophrenia (MIM 181500), [15][16][17][18][19][20][21][22][23][24][25][26][27] intellectual disability and language delay, epilepsy (MIM 614325), and attention deficit hyperactivity disorder (MIM 143465), 7,[28][29][30][31][32][33][34][35] suggesting that these deletions confer genetic risk across a broad range of neurodevelopmental and/or neuropsychiatric disorders. In addition to such variable expressivity, cases of incomplete penetrance and compound heterozygosity of NRXN1 deficiency have also been reported.…”

“…28,35 Unlike recurrent deletions mediated by flanking terminal repeats, NRXN1 deletions vary in size and location. 14,35 The observation of frequent rearrangement of NRXN1 suggests that it is peculiarly susceptible to mutational mechanisms that drive dosage imbalance and predispose individuals to risk of neuropsychiatric disorders. In this study, we examined two independent affected cohorts for the association of NRXN1 deletions with abnormal neurodevelopment and used deletion breakpoint mapping and sequence analysis to examine the characteristics of the mechanisms that underlie the nonrecurrent CNV formation in this gene.…”