Monozygotic twins with a de novo 0.32 Mb 16q24.3 deletion, includingTUBB3 presenting with developmental delay and mild facial dysmorphism but without overt brain malformation

AbstractDeletion of the region including chromosome 6p25 has been defined as a syndrome, with more than 68 reported cases. Individuals affected by the syndrome exhibit variable findings, including developmental delay and intellectual disability, cardiac anomalies, dysmorphic features, and—less commonly—skeletal and renal malformations. Ocular and hearing abnormalities are the most notable presenting features. The region encompasses more than 15 genes, of which the FOX group is the most likely causal factor of the clinical manifestations. We report the case of a 2-year-old child with developmental delay, generalized hypotonia, facial dysmorphism, and anomalies involving malformations of the eyes, heart, teeth, and skeleton. The magnetic resonance imaging (MRI) of the child's brain displayed cerebral anomalies involving the white matter, perivascular spaces, and corpus callosum. Array-CGH (comparative genomic hybridization) analysis displayed a de novo partial deletion of the short arm of chromosome 6, extending 5.13 Mb from nt 407.231 to nt 5.541.179. In infancy, neuroradiologic findings of abnormalities in the cerebral white matter and other neurologic anomalies elsewhere in the brain, in association with dysmorphisms and malformations, are highly suggestive of the diagnosis of 6p25 deletion syndrome. When these anomalies are found, the syndrome must be included in the differential diagnosis of disorders affecting the cerebral white matter.

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239-kb Microdeletion Spanning KMT2E in a Child with Developmental Delay: Further Delineation of the Phenotype

Molecular Syndromology ◽

10.1159/000516635 ◽

2021 ◽

pp. 1-6

Author(s):

Konstantina Kosma ◽

Konstantinos Varvagiannis ◽

Anastasios Mitrakos ◽

Maria Tsipi ◽

Joanne Traeger-Synodinos ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Common Mechanism ◽

Facial Dysmorphism ◽

Gi Symptoms

Pathogenic KMT2E variants underly O'Donnell-Luria-Rodan syndrome, a recently described neurodevelopmental disorder characterized by global developmental delay, variable degrees of intellectual disability, and subtle facial dysmorphism. Less common findings include autism, seizures, gastrointestinal (GI) problems, and abnormal head circumference. Occurrence of mostly truncating variants as well as the similar phenotype observed in individuals with deletions spanning KMT2E suggest haploinsufficiency of this gene as a common mechanism for the disorder, while a gain-of-function or dominant-negative effect cannot be ruled out for some missense variants. Deletions reported in the literature encompass several additional known or presumed haploinsufficient genes, thus leading to more complex phenotypes. Here, we describe a male with antenatal onset hydronephrosis, hypotonia, global developmental delay, prominent GI symptoms as well as facial dysmorphism. Chromosomal microarray revealed a 239-kb de novo microdeletion spanning KMT2E and LHFPL3. Clinical presentation of our proband, harboring one of the smallest deletions of the region confirms the core features of this disorder, suggests GI symptoms as a prominent finding in affected individuals while expanding the phenotypic spectrum to abnormalities of the urinary tract.

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Ocular Manifestations of a Novel Proximal 19p13.3 Microdeletion

Case Reports in Genetics ◽

10.1155/2018/2492437 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5

Author(s):

L. Swan ◽

D. Coman

Keyword(s):

Short Stature ◽

Developmental Delay ◽

Medical Literature ◽

De Novo ◽

Phenotypic Variability ◽

Clinical Manifestations ◽

Phenotypic Heterogeneity ◽

Facial Dysmorphism ◽

Ocular Manifestations

Microdeletions at 19p13.3 are rarely reported in the medical literature with significant phenotypic variability. Among the reported cases, common clinical manifestations have included developmental delay, facial dysmorphism, and hypotonia. Herein we described a child with a de novo 19p13.3 microdeletion, proximal to the reported cases of 19p13.3 microdeletion/duplication, with ocular manifestations of bilateral ocular colobomata complicated with microphthalmos and cataract, associated with short stature. This case highlights the phenotypic heterogeneity of deletions in the 19p13.3 region.

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A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review

Genes ◽

10.3390/genes12091388 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1388

Author(s):

Jiyoon Han ◽

Joonhong Park

Keyword(s):

Intellectual Disability ◽

Cerebral Infarction ◽

Exome Sequencing ◽

Developmental Delay ◽

Growth Retardation ◽

De Novo ◽

Confirmatory Test ◽

Chromosomal Microarray ◽

Facial Dysmorphism ◽

Coverage Analysis

The terminal 14q32 duplication has been reported often in association with other cytogenetic abnormalities, and individuals with this specific duplication showed varying degrees of developmental delay/intellectual disability (DD/ID) and growth retardation (GR), and distinct facial dysmorphisms. Herein, based on the limited cases of terminal duplication of 14q32 known to date, we present new affected siblings presenting with DD/ID, GR, and facial dysmorphism, as well as cerebral infarction caused by recurrent de novo der(14)t(14;14)(p11.2;q32.1) leading to terminal duplication of 14q32. We used coverage analysis generated via duo exome sequencing, performed chromosomal microarray (CMA) as a confirmatory test, and compared our findings with those reported previously. Coverage analysis generated via duo exome sequencing revealed a 17.2 Mb heterozygous duplication at chromosome 14q32.11-q32.33 with a Z ratio ranging between 0.5 and 1 in the proband and her elder brother. As a complementary method, CMA established a terminal duplication described as the arr[hg19]14q32.11q32.33(90,043,558_107,258,824)x3 in the proband and her elder brother; however, the parents and other siblings showed normal karyotyping and no abnormal gain or loss of CMA results. Five candidate genes, BCL11B, CCNK, YY1, DYNC1H1, and PACS2, were associated with the clinical phenotypes in our cases. Although the parents had normal chromosomes, two affected cases carrying terminal duplication of 14q32 can be explained by gonadal mosaicism. Further studies are needed to establish the association between cerebrovascular events and terminal duplication of chromosome 14q32, including investigation into the cytogenetics of patients with precise clinical descriptions.

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De Novo Nonsense Variant in ASXL3 in a Chinese Girl Causing Bainbridge–Ropers Syndrome: A Case Report and Review of Literature

10.21203/rs.3.rs-810120/v1 ◽

2021 ◽

Author(s):

Qin Wang ◽

Jianming Zhang ◽

Nan Jiang ◽

Jiansheng Xie ◽

Jingxin Yang ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Developmental Delay ◽

Sanger Sequencing ◽

De Novo ◽

Clinical Symptoms ◽

Failure To Thrive ◽

Varus Deformity ◽

Facial Dysmorphism ◽

Loss Of Function ◽

Chinese Girl

Abstract Background: Bainbridge-Ropers syndrome (BRPS, OMIM #615485) was first identified in 2013 by Bainbridge et al. and is a neurodevelopment disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay. BRPS is caused by heterozygous loss-of function (LOF) variants in the additional sex combs-like 3 (ASXL3) gene which are mostly located in two mutational cluster regions (MCR). Due to the limited specific recognizable features and overlapping symptoms with Bohring–Opitz syndrome, clinical diagnosis of BRPS is challenging. Case presentation: In this study, a 2-year-8-month-old Chinese girl was referred for genetic evaluation of severe developmental delay. Reduced fetal movement was found during antenatal period and bilateral varus deformity of feet was observed at birth. Whole exome sequencing and Sanger sequencing were used to detect and confirm the variant. A novel nonsense variant c.1063G>T (p.E355X) in the ASXL3 gene (NM_030632.3) was identified in the proband and the clinical symptoms were compatible with BRPS. The parents were physical and genetic normal and prenatal diagnosis was requested for her pregnant mother with a negative Sanger sequencing result. Conclusion: The study revealed a de novo LOF variant in the ASXL3 gene and expanded the mutation spectrum for this clinical condition. By performing a literature review, we analyzed the clinical phenotype with limited fetal features and summarized genetic results of all BPRSs reported so far. More cases study may help to elucidate the function of ASXL3 gene that may be critical to understand the genetic etiology of this syndrome and assist in accurate genetic counselling, informed decision making and prenatal diagnosis.

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Developmental delay and facial dysmorphism in a child with an 8.9 Mb de novo interstitial deletion of 3q25.1–q25.32: Genotype–phenotype correlations of chromosome 3q25 deletion syndrome

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2010.11.011 ◽

2011 ◽

Vol 54 (2) ◽

pp. 177-180 ◽

Cited By ~ 6

Author(s):

Stephanie Moortgat ◽

Christine Verellen-Dumoulin ◽

Isabelle Maystadt ◽

Benoit Parmentier ◽

Bernard Grisart ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Interstitial Deletion ◽

Deletion Syndrome ◽

Facial Dysmorphism

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Jacobsen syndrome and neonatal bleeding: report on two unrelated patients

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01108-2 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Gregorio Serra ◽

Luigi Memo ◽

Vincenzo Antona ◽

Giovanni Corsello ◽

Valentina Favero ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Comparative Genomic ◽

Fish Analysis ◽

Variable Degree ◽

Jacobsen Syndrome ◽

Contiguous Gene ◽

Clinical Consequences ◽

11Q Deletion

Abstract Introduction In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. Patients’ presentation We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. Conclusions Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

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