Multisystem Developmental Disorder Research Articles

Spectrum and consequences ofSMC1Amutations: The unexpected involvement of a core component of cohesin in human disease

SMC1A encodes a structural component of the cohesin complex, which is necessary for sister chromatid cohesion. In addition to its canonical role, cohesin has been shown to be involved in gene expression regulation and maintenance of genome stability. Recently, it has been demonstrated that mutations in the SMC1A gene are responsible for Cornelia de Lange syndrome (CdLS). CdLS is a genetically heterogeneous multisystem developmental disorder with variable expressivity, typically characterized by consistent facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, gastrointestinal abnormalities, and other systemic involvement. SMC1A mutations have also been identified in colorectal cancers. So far a total of 26 different mutations of the SMC1A gene have been reported. All mutations reported to date are either missense or small in-frame deletions that maintain the open reading frame and presumably result in a protein with residual function. The mutations involve all domains of the protein but appear to cluster in key functional loci. At the functional level, elucidation of the effects that specific SMC1A mutations have on cohesin activity will be necessary to understand the etiopathology of CdLS and its possible involvement in tumorigenesis. In this review, we summarize the current knowledge of SMC1A mutations.

Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells

Author SummaryAppropriate segregation of chromosomes to daughter cells depends upon proper cohesion of sister chromatids during mitosis. The multiprotein cohesin complex and its regulators are key factors in this process. Intriguingly, recent work has shown that the cohesin complex also has other cellular roles, including a role in regulating gene expression. Additionally, mutations in cohesin structural and regulatory components have been linked to human multisystem developmental disorders such as Cornelia de Lange Syndrome (CdLS), but the role cohesin is playing in the pathogenesis of this disorder is unknown. To define the role that cohesin plays in regulating gene expression in human cells, we analyzed gene expression and genome-wide cohesin binding patterns in cells from normal subjects and from CdLS probands with mutations in the cohesin regulator NIPBL or in the cohesin structural component SMC1A. We found a strikingly conserved pattern of gene dysregulation in these different cell lines that correlates with disease severity and a significant correlation between gene dysregulation and cohesin binding around misexpressed genes. The observed pattern of binding and misexpression is consistent with cohesin having a putative role as a boundary/insulator interacting protein or transcription factor, the activity of which is disrupted in CdLS probands.

29개월 된 중다체계 발달장애 유아의 놀이치료 사례

29개월 된 중다체계 발달장애 유아의 놀이치료 사례

A newborn with Cornelia de Lange syndrome: a case report

Cornelia de Lange syndrome (CdLS) is a rarely seen multisystem developmental disorder syndrome characterized by facial dysmorphia (arched eyebrows, synophrys, depressed nasal bridge, long philtrum, down-turned angles of the mouth), upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. The features of this disorder vary widely among affected individuals and range from relatively mild to severe. Early in life, the distinctive craniofacial features in mild de Lange syndrome may be indistinguishable from the severe (classical) phenotype. We present here a case of newborn with CdLs.

Incidence and clinical features of X-linked Cornelia de Lange syndrome due toSMC1L1 mutations

Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Heterozygous mutations in the NIPBL gene have been detected in approximately 45% of affected individuals. Recently, a second CdLS gene, mapping to the X chromosome, has been identified: SMC1L1 (structural maintenance of chromosomes 1-like 1; or SMC1A). In order to estimate the incidence and refine the clinical presentation of X-linked CdLS, we have screened a series of 11 CdLS boys carrying no NIPBL anomaly. We have identified two novel de novo SMC1L1 missense mutations (c.587G>A [p.Arg196His] and c.3254A>G [p.Tyr1085Cys]). Our results confirm that SMC1L1 mutations cause CdLS and support the view that SMC1L1 accounts for a significant fraction of boys with unexplained CdLS. Furthermore, we suggest that SMC1L1 mutations have milder effects than NIPBL mutations with respect to pre- and postnatal growth retardation and associated malformations. If confirmed, these data may have important implications for directing mutation screening in CdLS.

Echocardiographic findings in patients with Williams-Beuren syndrome

Williams-Beuren syndrome is a multisystem developmental disorder caused by a microdeletion at chromosome 7q11.23. In its classic form it includes dysmorphic facial features, joint contractures, retardation of growth and mental development, gregarious personality, visuospatial cognitive deficits, hypercalcemia, primary or secondary hypertension and cardiovascular disorders. Clinical diagnosis of Williams-Beuren syndrome can be a challenge in young patients if none of the characteristic cardiovascular features, i.e. supravalvular aortic stenosis or pulmonary artery stenosis, are present. Our aim was to demonstrate the changes in cardiovascular lesions during the postnatal development of Williams-Beuren patients and to follow all cardiovascular findings beyond the most common ones. The cardiovascular status of 29 patients with Williams-Beuren syndrome (mean age 12.8 years) was recorded in correlation with age. Cardiovascular diagnoses changed in the majority (72.4%) of patients. Interestingly, 44.8% of the patients had periods with no reported cardiovascular disease. Furthermore, 65.5% of the patients experienced periods when none of the typical cardiovascular lesions, i.e. diffuse or localized supravalvular aortic stenosis and/or pulmonary artery stenosis, were detected. Spontaneous regression and progression of both supravalvular aortic stenosis and pulmonary artery stenosis were observed. An unexpectedly high frequency (41%) of mitral valve disorders was found. Our study showed that temporary absence of and changes in cardiovascular findings are frequent in Williams-Beuren syndrome. These results could contribute to the refinement of diagnostic criteria and recommendations for cardiovascular follow-up of patients with this syndrome.

X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations

Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmorphisms, upper limb abnormalities, growth delay and cognitive retardation. Mutations in the NIPBL gene, a component of the cohesin complex, account for approximately half of the affected individuals. We report here that mutations in SMC1L1 (also known as SMC1), which encodes a different subunit of the cohesin complex, are responsible for CdLS in three male members of an affected family and in one sporadic case.

Precocious sister chromatid separation (PSCS) in Cornelia de Lange syndrome

The Cornelia de Lange syndrome (CdLS) (OMIM# 122470) is a dominantly inherited multisystem developmental disorder. The phenotype consists of characteristic facial features, hirsutism, abnormalities of the upper extremities ranging from subtle changes in the phalanges and metacarpal bones to oligodactyly and phocomelia, gastroesophageal dysfunction, growth retardation, and neurodevelopmental delay. Prevalence is estimated to be as high as 1 in 10,000. Recently, mutations in NIPBL were identified in sporadic and familial CdLS cases. To date, mutations in this gene have been identified in over 45% of individuals with CdLS. NIPBL is the human homolog of the Drosophila Nipped-B gene. Although its function in mammalian systems has not yet been elucidated, sequence homologs of Nipped-B in yeast (Scc2 and Mis4) are required for sister chromatid cohesion during mitosis, and a similar role was recently demonstrated for Nipped-B in Drosophila. In order to evaluate NIPBL role in sister chromatid cohesion in humans, metaphase spreads on 90 probands (40 NIPBL mutation positive and 50 NIPBL mutation negative) with CdLS were evaluated for evidence of precocious sister chromatid separation (PSCS). We screened 50 metaphases from each proband and found evidence of PSCS in 41% (compared to 9% in control samples). These studies indicate that NIPBL may play a role in sister chromatid cohesion in humans as has been reported for its homologs in Drosophila and yeast.

NIPBL Mutational Analysis in 120 Individuals with Cornelia de Lange Syndrome and Evaluation of Genotype-Phenotype Correlations

The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.

Diagnostic boundaries between regulatory and multisystem developmental disorders: A clinical study

AbstractThe objective of the study was to define diagnostic boundaries between Regulatory Disorders (RD) and Multisystem Developmental Disorders (MSDD). Two groups of 15 subjects, between 20 and 36 months of age, diagnosed as RD or MSDD, according to DC: 0–3 (1994) criteria, were compared in relationship, linguistic, and behavioral profiles using specific instruments. The results showed that both RD and MSDD children were impaired on all linguistic measures with a higher significant impairment of MSDD for communicative gestures, spontaneous speech, and verbal comprehension. The Child Behavior Checklist (CBCL) showed significant differences for withdrawn, and somatic problems. Only the MSDD group reached the clinical cutoff score in total problems, internalizing and withdrawn behaviors. A discriminate analysis showed that the number of communicative gestures and the scores on withdrawn and somatic problems correctly predicted in 86% of cases. It was concluded that RD and MSDD children show quantitative and qualitative differences in many of the linguistic, behavioral, and relational dimensions that were explored. These dimensions may facilitate the differential diagnosis of these disorders. ©2003 Michigan Association for Infant Mental Health.

Integration of a c-myc Transgene Results in Disruption of the Mouse Gtf2ird1 Gene, the Homologue of the Human GTF2IRD1 Gene Hemizygously Deleted in Williams–Beuren Syndrome

Transgenic mice expressing c-myc under the control of the albumin promoter and enhancer develop liver tumors and have served as a useful model for studying the progression of hepatocarcinogenesis. The chromosomes of one line of c-myc transgenic mice carry the reciprocal translocation t(5;6)(G1;F2) adjacent to the transgene insertion site on the 5G1–ter segment translocated to chromosome 6. To characterize the genomic alterations in the c-myc transgenic animals, we have cloned the mouse DNA flanking the transgene array. By linkage mapping, the transgene integration site was localized to the region of distal chromosome 5 syntenic to the region on human chromosome 7q11.23 that is hemizgygously deleted in Williams–Beuren syndrome, a multisystemic developmental disorder. Comparison of the genomic DNA structure in wildtype and transgenic mice revealed that the transgene integration had induced an ∼40-kb deletion, starting downstream of the Cyln2 gene and including the first exon of the Gtf2ird1 gene. Gtf2ird1 encodes a polypeptide related to general transcription factor TFII-I, and it is the mouse orthologue of GTF2IRD1 (WBSCR11), one of the genes commonly deleted in Williams–Beuren syndrome patients. Loss of the 5′ end of the Gtf2ird1 gene resulted in greatly reduced expression of Gtf2ird1 mRNA in mice homozygous for the transgene.

The differential diagnosis of impaired reciprocal social interaction in children: a review of disorders.

Impairment in reciprocal social interaction in children that is less severe than autism can be difficult to diagnose due to the variety of developmental pathways that may lead to this problem. Seven childhood disorders are reviewed that include impaired reciprocal interaction: multisystem developmental disorder, nonverbal learning disability syndrome, semantic-pragmatic disorder, attachment disorders (including a developmental theory of limbic system damage), multiplex developmental disorder, schizoid personality disorder, and pervasive developmental disorder not otherwise specified. Clarification is needed for most of the disorders in the areas of operationalized criteria, assessment tools, and documenting causal relationships.

Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations.

Optic nerve coloboma combined with renal disease, also called renal-coloboma syndrome ( # 120330 in McKusick's Mendelian Inheritance in Man Online, OMIM), a relatively recently characterized syndrome, results from autosomal dominant mutations in the PAX2 gene. Although renal-coloboma syndrome involves both ocular and renal anomalies, some patients are affected with vesico-ureteral reflux (VUR), high frequency hearing loss, central nervous system (CNS) anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development. We review here the clinical features of patients with renal-coloboma syndrome and PAX2 mutation. We also review the PAX2 mutations that have been reported to date, and discuss the possible effect of PAX2 mutations on normal development.

Molecular analysis of human Jaggedl gene in an Indian family with Alagille syndrome

Alagille syndrome (AGS), a multisystem developmental disorder, is characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae and a characteristic facial appearance. The AGS phenotype has been associated with mutations in the Jaggedl gene (JAGI) which encodes a ligand in the Notch signalling pathway that is important in cell-fate determination in a number of tissues.We report an Indian family with a two year old male proband presenting severe AGS with marked hypercholesterolemia while the mother presented only characteristic facial phenotype but normal liver and kidney function. Mutation screening of all 26 exons of JAGI identified a 2841insA mutation in exon 21 (codon 824) in the patient. This mutation is predicted to cause a premature termination of translation of protein within the same codon. The mutated termination codon occurs within the EGF-like repeats domain of the JAGI protein. This domain is highly conserved between Drosophila, rat and human, and is thought to be one of the regions which play a critical role in ligand-receptor interactions. Direct sequencing of genomic DNA from the mother of the patient failed to reveal the presence of the 2841insA mutation. As the 2841insA mutation abolishes a cutting site for Bsm1, this restriction enzyme was also used to confirm the absence of this mutation in the mother. Our data show that that factors not attributable to the specific 2841insA mutation must play a role in determination of the subclinical AGS phenotype seen in the mother.

Identification of Genes from a 500-kb Region at 7q11.23 That Is Commonly Deleted in Williams Syndrome Patients

Williams syndrome (WS) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Hemizygosity of the elastin (ELN) gene can account for the vascular and connective tissue abnormalities observed in WS patients, but the genes that contribute to features such as infantile hypercalcemia, dysmorphic facies, and mental retardation remain to be identified. In addition, the size of the genomic interval commonly deleted in WS patients has not been established. In this study we report the characterization of a 500-kb region that was determined to be deleted in our collection of WS patients. A detailed physical map consisting of cosmid, P1 artificial chromosomes, and yeast artificial chromosomes was constructed and used for gene isolation experiments. Using the techniques of direct cDNA selection and genomic DNA sequencing, three known genes (ELN, LIMK1, and RFC2), a novel gene (WSCR1) with homology to RNA-binding proteins, a gene with homology to restin, and four other putative transcription units were identified. LIMK1 is a protein kinase with two repeats of the LIM/double zinc finger motif, and it is highly expressed in brain. RFC2 is the 40-kDa ATP-binding subunit of replication factor C, which is known to play a role in the elongation of DNA catalyzed by DNA polymerase δ and ϵ. LIMK1 and WSCR1 may be particularly relevant when explaining cognitive defects observed in WS patients.

Integrated treatment approaches for young children with multisystem developmental disorder

ABSTRACTYoung children with severe communication and relationship disorders, often diagnosed with pervasive developmental disorders, respond to intensive intervention started at early ages. These disorders may be secondary to various sensory and motor processing deficits which can be conceptualized