Elizabeth McCready

Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression

Purpose:The purpose of the current study was to assess the penetrance of NRXN1 deletions.Methods:We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions.Results:We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91–22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3ʹ end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5ʹ NRXN1 deletion (OR = 7.47; 95% CI: 2.36–23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035).Conclusions:The results support the importance of exons near the 5ʹ end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53–61.

Müllerian Agenesis in Cat Eye Syndrome and 22q11 Chromosome Abnormalities: A Case Report and Literature Review

BACKGROUND Although Müllerian agenesis is the second most common cause of primary amenorrhea the underlying etiology in most cases is unknown. Müllerian agenesis has been reported as a rare finding associated with chromosomal aberrations of the 22q11 chromosomal region including at least 1 individual with cat eye syndrome (CES) and 10 individuals with deletions or duplications of the 22q11.2 region. However, a potential link between 22q11 abnormalities and uterine malformations has been difficult to adequately ascertain because of the limited case reports in the literature. CASE We report a second case of Müllerian agenesis in a girl with CES. A 16-year-old girl presented with bilateral colobomata, primary amenorrhea, and absence of the uterus and upper vagina on pelvic magnetic resonance imaging. Microarray analysis showed tetrasomy of the pericentromeric region of chromosome 22 diagnostic of CES. SUMMARY AND CONCLUSION Müllerian aplasia/hypoplasia might represent a rare feature in CES and should be considered in the investigation of young girls with this syndrome. An increasing number of cases with 22q11 chromosome abnormalities and Müllerian agenesis further highlights the possibility of a gene within the 22q11 region that might mediate normal Müllerian development in girls.

Prader–Willi syndrome and Tay–Sachs disease in association with mixed maternal uniparental isodisomy and heterodisomy 15 in a girl who also had isochromosome Xq

Malsegregation of chromosomes during reproduction can result in uniparental disomy when associated with trisomy rescue, monosomy rescue or gamete complementation. Pathogenicity stemming from uniparental disomy in liveborns results from imprinting disorders or autozygosity for autosomal recessive disorders. We report on a girl with Prader–Willi syndrome and Tay–Sachs disease resulting from maternal uniparental disomy of chromosome 15. The child also had an isochromosome Xq. To further characterize the etiology of the aberrant chromosome 15 and the isochromosome Xq, SNP loci from both chromosomes were assessed in the proband and parents, and genome‐wide DNA methylation analysis was performed. SNP and DNA methylation analysis confirmed maternal uniparental heterodisomy around the Prader–Willi locus, while the region around the HEXA locus showed maternal uniparental isodisomy. This result is consistent with trisomy rescue of a maternal meiosis l error in a chromosome 15 with two meiotic recombinations. SNP analysis of the X chromosomes is consistent with a maternal origin for the isochromosome.

Changes in expression of the CD200 tolerance-signaling molecule and its receptor (CD200R) by villus trophoblasts during first trimester missed abortion and in chronic histiocytic intervillositis

Expression of CD200 at the feto‐maternal interface is associated with successful murine and human pregnancy. CD200 binding to CD200 receptors on lymphomyeloid cells suppresses inflammation and induces Tregs. CD200 receptors are also expressed on mouse and human placental trophoblast cells. What is the expression of CD200 and CD200R in human missed abortions which have preserved Treg levels and in chronic histiocytic intervillositis (CHI) where maternal inflammatory cells cause IUGR?

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Purpose To assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations. Methods We analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations. Results The number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes. Conclusion Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

PurposeTo assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants.MethodsWe analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants.ResultsThe number of rare likely deleterious variants in functionally intolerant genes (“other hits”) correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

Partial monosomy 1q43 and partial trisomy 20q13.2: a case report.

BHSc Program, Faculty of Health Sciences, and Departments of Pathology and Molecular Medicine and Pediatrics, McMaster University, Hamilton, Ontario, Canada Correspondence to Malgorzata J.M. Nowaczyk, MD, Department of Pathology and Molecular Medicine, McMaster University Medical Centre, 1200 Main Street West, Room 3N16, Hamilton, ON, Canada L8S 4J9 Tel: + 1 905 521 5085; fax: + 1 905 521 2651; e-mail: nowaczyk@hhsc.ca

MG-123 Exonic and intronic NRXN1 deletions: Novel genotype-phenotype correlations

Objectives To 1) further characterise the extended phenotype of exonic NRXN1 deletions and 2) systematically evaluate the pathogenicity of intronic NRXN1 deletions in order to help inform clinical diagnostic practice. Methods We examined clinically ascertained cases from three Canadian cytogenetic laboratories for exonic NRXN1 deletions. Referring physicians completed a clinical checklist to identify major lifetime features and illnesses. One lab’s clinically referred cases were available to investigate the prevalence of intronic NRXN1 deletions in comparison to 15,254 controls. Genome-wide CNV data from high-resolution microarrays were investigated for the presence of additional rare variants. Results We identified 41 (0.21%) exonic NRXN1 deletions among 19,263 clinically referred cases, an over eight-fold increase compared to controls (p < 0.0001). Novel phenotypes identified in two or more exonic NRXN1 deletion cases included nine adults with comorbid intellectual disability and a psychiatric illness, movement disorders, automutilation, sleep disorders, and obsessions and preoccupations. The prevalence of congenital anomalies was low. The prevalence of intronic NRXN1 deletions did not differ between clinical cases (19/6,022; 0.32%) and controls (55/15,524; 0.35%). Additional pathogenic rare variants were four times more common in intronic (n = 6/19; 31.6%) compared to exonic (n = 3/41; 7.3%) NRXN1 deletion cases. Conclusions The expression of exonic NRXN1 deletions is primarily neuropsychiatric and may be associated with comorbid intellectual disability and a psychiatric illness in adulthood. To our knowledge this is the first study to demonstrate that the majority of intronic NRXN1 deletions by themselves are unlikely to cause clinical phenotypes, however further study on their potential functional impact is needed.

MG-121 Complexity of phenotypes of females with unbalanced x-autosomal translocations exemplified by a case with 46, x,der (x)t (x;16)(p11.2;p13.2) karyotype

Background Females with unbalanced X-autosomal translocations frequently exhibit skewed X-chromosome inactivation, as cells with the least functional imbalance have selective advantage. However, predicting the inactivation status of the translocated autosomal segment and its impact on phenotype is challenging. Active vs inactive state can depend on translocation breakpoint and sequence features of the translocated segment. Objective Report a case with 46,X,der (X)t (X;16)(p11.2;p13.2) karyotype and discuss karyotype/phenotype correlations. Results We report a 18 month old girl with intrauterine growth restriction, failure to thrive, cardiac anomalies and dysmorphic features. Oligonucleotide microarray has revealed a terminal ~9 Mb gain of chromosome 16p and terminal loss of most of Xp. A de novo unbalanced translocation t (X;16)(p11.2;p13.2) was confirmed by karyotype analysis and family studies. Androgen receptor assay further showed complete skewing of X-inactivation, suggesting that derivative X-chromosome was inactive. Phenotype of our patient was not fully consistent with either Xp deletion or 16p13.3 duplication, leaving a question about inactivation status of the translocated 16p material. A case with 46, X,der (X) t (X;16)(q28;p12) karyotype and phenotype consistent with 16p13.3 duplication syndrome was previously reported. Replication studies have shown skewed inactivation of the der (X), not spreading into 16p translocated segment.1 Conclusions Our patient phenotype suggests that while Androgen Receptor assay provides valuable information in regard of X-inactivation skewing, it has limitations for karyotype/phenotype correlations for patients with unbalanced X-autosomal translocation. Additional analysis of inactivation status of the genes of the translocated segment is underway to understand the phenotype of our patient. Reference Preis W, Barbi G, Liptay S, Kennerknecht I, Schwemmle S, Pohlandt F. X/autosome translocation in three generations ascertained through an infant with trisomy 16p due to failure of spreading of X-inactivation. Am J Med Genet. 1996;61(2):117–21