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Facial features of the patients Facial features of patients 1 to 3 from left to right. Note short neck, slight unilateral ptosis, downward slant of the palpebral fissures, narrow nose, small nares, long philtrum with a narrow deep groove, tented upper lip, ears with broad helices and uplifted lobuli.
Source publication
Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309).
We report two mentally retarded female siblings and their cognitively normal father, all carrying a...
Citations
... Interstitial deletions of the long arm of chromosome 9 have been reported in the context of many types of cancer and congenital syndromes with variation in size and location [Midro et al., 2004;Gamerdinger et al., 2008;Kulharya et al., 2008;Siggberg et al., 2011]. ...
Introduction:
Patients carrying interstitial deletions of the long arm of chromosome 9 show similar features. These phenotypes are often characterized by developmental delay, intellectual disability, short stature, and dysmorphism. Previously reported deletions differ in size and location spanning from 9q21 to 9q34 and were mostly detected by conventional cytogenetic techniques.
Methods:
Based on clinical features suggesting primarily chromosomal diseases, aCGH analysis was indicated. We report on de novo overlapping interstitial 9q deletions in 3 unrelated individuals presenting neurodevelopmental disorder and multiple congenital anomalies.
Results:
An 8.03-Mb (90 genes), a 15.71-Mb (193 genes), and a 15.81-Mb (203 genes) deletion were identified in 9q affecting 9q22.33q33.3. The overlapping region was 1.50 Mb, including 2 dosage-sensitive genes, namely EPB41L4B (OMIM #610340) and SVEP1 (OMIM #611691). These genes are thought to be involved in cellular adhesion, migration, and motility. The non-overlapping regions contain 24 dosage-sensitive genes.
Conclusion:
Besides the frequently described symptoms (developmental delay, intellectual disability, skeletal abnormalities, short stature, and dysmorphic facial features) shared by the patients with interstitial deletions of chromosome 9q reported thus far, two of our patients showed distinct forms of epilepsy, which were successfully treated, and one had a bilateral cleft lip and palate. Possible candidate genes for epilepsy and cleft lip and palate are discussed.
... However, it is sometimes possible to find information in cytogenetic studies which could provide some insight regarding imprinting of genomic regions. For example, for 9q22, some deletions (not all involving PTCH1) associated with language delay or intellectual disability are of paternal origin, suggesting that the paternal allele is expressed in that region [59,60]. This does not mean that the maternal allele is not expressed. ...
Background:
One of the most basic human traits is language. Linguistic ability, and disability, have been shown to have a strong genetic component in family and twin studies, but molecular genetic studies of language phenotypes are scarce, relative to studies of other cognitive traits and neurodevelopmental phenotypes. Moreover, most genetic studies examining such phenotypes do not incorporate parent-of-origin effects, which could account for some of the heritability of the investigated trait. We performed a genome-wide association study of receptive language, examining both child genetic effects and parent-of-origin effects.
Results:
Using a family-based cohort with 400 children with receptive language scores, we found a genome-wide significant paternal parent-of-origin effect with a SNP, rs11787922, on chromosome 9q21.31, whereby the T allele reduced the mean receptive language score by ~ 23, constituting a reduction of more than 1.5 times the population SD (P = 1.04 × 10-8). We further confirmed that this association was not driven by broader neurodevelopmental diagnoses in the child or a family history of psychiatric diagnoses by incorporating covariates for the above and repeating the analysis.
Conclusions:
Our study reports a genome-wide significant association for receptive language skills; to our knowledge, this is the first documented genome-wide significant association for this phenotype. Furthermore, our study illustrates the importance of considering parent-of-origin effects in association studies, particularly in the case of cognitive or neurodevelopmental traits, in which parental genetic data are not always incorporated.
... Mutations in the SECIBP2 and AUH genes are associated with autosomal recessive conditions: an abnormal thyroid metabolism disorder and type 1 methylglutaconic aciduria, respectively. [8][9][10] The NTRK2 (neurotrophic receptor tyrosine kinase 2) gene localizes to chromosome 9q21.33 and contains 23 exons. ...
... Twenty-eight cases of interstitial 9q deletions were found span, flanked, or partially overlapped with the current case's deletion. [8][9][10][22][23][24][25][26][27][28][29][30][31][32][33][34] The clinical features of individuals with deletion of 9q varied with few common features. ...
Cytogenomic microarray (CMA) methodologies, including array comparative genomic hybridization (aCGH) and single-nucleotide polymorphism-detecting arrays (SNP-array), are recommended as the first-tier test for the evaluation of imbalances associated with intellectual disability, autism, and multiple congenital anomalies. The authors report on a child with global developmental delay (GDD) and a de novo interstitial 7.0 Mb deletion of 9q21.33q22.31 detected by aCGH. The patient that the authors report here is noteworthy in that she presented with GDD and her interstitial deletion is not inclusive of the 9q22.32 locus that includes the PTCH1 gene, which is implicated in Gorlin syndrome, or basal cell nevus syndrome (BCNS), has not been previously reported among patients with a similar or smaller size of the deletion in this locus suggesting that the genomic contents in the identified deletion on 9q21.33q22.31 is critical for the phenotype.
... Pleotropic kidney defects, including cystic kidney disease [2], hypoplastic kidney [13], hydronephrosis and nephrocalcinosis [14] have been reported in patients with Robinow syndrome. Wnt5a has been found to play important roles in these patients' craniofacial and skeletal abnormalities. ...
Background:
Wnt5a is important for the development of various organs and postnatal cellular function. Little is known, however, about the role of Wnt5a in kidney development, although WNT5A mutations were identified in patients with Robinow syndrome, a genetic disease which includes developmental defects in kidneys. Our goal in this study was to determine the role of Wnt5a in kidney development.
Methods:
Whole-mount in situ hybridization was used to establish the expression pattern of Wnt5a during kidney development. Zebrafish with wnt5a knockdown and Wnt5a global knockout mice were used to identify kidney phenotypes.
Results:
In zebrafish, wnt5a knockdown resulted in glomerular cyst formation and dilated renal tubules. In mice, Wnt5a global knockout resulted in pleiotropic, but severe, kidney phenotypes, including agenesis, fused kidney, hydronephrosis and duplex kidney/ureter.
Conclusions:
Our data demonstrated the important role of Wnt5a in kidney development. Disrupted Wnt5a resulted in kidney cysts in zebrafish and pleiotropic abnormal kidney development in mice.
... The deletion involves 30 genes, including the immunologically active SYK gene. 5 Fostamatinib 1, a poorly selective Syk inhibitor, recently completed phase II trials for the treatment of rheumatoid arthritis ( Figure 1). 6 In these studies adverse effects included hypertension, gastrointestinal effects (nausea and diarrhea), and neutropenia. ...
A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed Phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis, and offer useful guidance to other researchers in the field.
Background
Pectus excavatum (PE) could be part of a genetic disorder, which then has implications regarding comorbidity, the surgical correction of PE, and reproductive choices. However, referral of a patient presenting with PE for genetic analysis is often delayed because additional crucial clinical signs may be subtle or even missed in syndromic patients. We reviewed the literature to inventory known genetic disorders associated with PE and create a standardized protocol for clinical evaluation.
Methods
A systematic literature search was performed in electronic databases. Genetic disorders were considered associated with PE if studies reported at least five cases with PE. Characteristics of each genetic disorder were extracted from the literature and the OMIM database in order to create a practical guide for the clinician.
Results
After removal of duplicates from the initial search, 1632 citations remained. Eventually, we included 119 full text articles, representing 20 different genetic disorders. Relevant characteristics and important clinical signs of each genetic disorder were summarized providing a standardized protocol in the form of a scoring list. The most important clinical sign was a positive family history for PE and/or congenital heart defect.
Conclusions
Twenty unique genetic disorders have been found associated with PE. We have created a scoring list for the clinician that systematically evaluates crucial clinical signs, thereby facilitating decision making for referral to a clinical geneticist.
Songbird vocal learning depends on the anterior forebrain pathway, the organization of which reflects a conserved vertebrate cortico-basal ganglia-thalamocortical loop architecture. We review the involvement of FoxP2 in this circuit, as well as FoxP1 and Cntnap2, both posited to participate alongside FoxP2. In the avian striatum, FoxP2 expression is regulated by singing, highlighting the possibility that developmental verbal dyspraxia arising from human FOXP2 mutation might primarily reflect a deficit in ongoing neural signaling, rather than developmental miswiring. We explore genes co-regulated with FoxP2 during singing and propose that Wnt trafficking and p63 signaling pathways may be crucial to speech and language. © 2013 Springer Science+Business Media New York. All rights are reserved.
Insertions are rare chromosomal rearrangements resulting from a three breaks mechanism. The risk of chromosomal imbalance in the offspring is estimated to be 15-50%. We have identified a familial history of direct, paracentric intrachromosomal 9q insertion, balanced in healthy members. For intrachromosomal insertions, unbalanced products in the offspring are always recombinants and in our case, reciprocal deletion and duplication of the inserted segment (9q22.31-9q31.1) were observed. These imbalances involved several genes, including PTCH1. PTCH1 haploinsufficiency causes Gorlin syndrome, an autosomal dominant disorder usually linked to the gene mutation but sometimes due to a 9q deletion. Clinical findings are different in 9q deletions and duplications including PTCH1, notably concerning the predisposition to benign and malignant tumors reported in the Gorlin syndrome. Furthermore, some features may be reciprocal. This history of intrachromosomal insertion highlights the importance of morphological cytogenetic analyses to provide an accurate genetic counseling.
This study was aimed at estimating the frequency of unbalanced structural chromosomal anomalies identified in the consecutive series of newborn infants with congenital defects, registered in the Spanish Collaborative Study of Congenital Malformations (ECEMC). These cases were cytogenetically studied at its laboratory since 1981 up to December 2009. A total of 4,681 cases were studied following a protocol established by ECEMC program, which starts by performing a high resolution karyotype (550-850 bands), and if the results are normal, it is followed by the analysis of subtelomeric regions and depending on the clinical manifestations, some FISH and MLPA analyses were applied in order to also rule out microdeletion syndromes. The parents and other relatives were also studied when necessary, according to ECEMC’s protocol. A total of 136 cases had unbalanced chromosomal structural anomalies. Data were analyzed either globally or in two periods including the years 1981-1994, and 1995-2009 which are before and after starting the use of FISH techniques in the ECEMC`s laboratory.
Among the 136 total cases having unbalanced structural anomalies, 71.32% were cytogenetically detected, and the remaining 28.68% by FISH. Each type of anomaly was distributed by involved chromosome separating those affecting p and q arms. In the group of cytogenetically detected anomalies, deletions (42.55% of cases) were 2.1 times more frequent than duplications (20.22%). Deletions affecting short arms were 3 times more frequent than duplications. Among cases detected by FISH techniques, deletions were 15.49 times more frequent than duplications, the 22q11.2 microdeletion being the most common (38.46% of the cases), followed by the deletions in chromosomes 15 (15.38%) and 4 (10.26%). Some of these alterations were identified by the clinical suspicion of their specific syndromes (Wolf-Hirschhorn, Prader-Willi, Williams-Beuren, Miller-Dieker, etc), and this could somehow bias their frequencies (see Table 3). In addition, some other unexpected microdeletion syndromes were detected such as two cases with microdeletion 1p36, one case with each of the following microdeletions: 2q23.1, 5q31, and a microdeletion 12q13.3-q21.2, including the region of the known microdeletion syndrome 12q14, but it is possible that may be other not hitherto identified.
To our knowledge, this study represents the first one analyzing the frequency of chromosomal alterations globally and by each one of the 23 chromosomes on a consecutive series of newborn infants with congenital defects which are detectable during the first three days of life. It is also remarkable that all the cases were studied with the same protocol and the same team of specialists.
