Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the MEF2C gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype. To date, nearly 40 cases have been reported; the deletion size and clinical spectrum are variable, and at least 6 cases without MEF2C involvement have been documented. We herein report the clinical and cytogenomic findings of an 11-year-old girl who has a 5q14.3q21.1 de novo deletion that does not involve MEF2C but shares the clinical features described in other reported patients. Moreover, she additionally presents with bilateral cleft-lip palate (CLP), which has not been previously reported as a feature of the syndrome. The most frequent syndromic forms of CLP were ruled out in our patient mainly by clinical examination, and Sanger sequencing was performed to discard the presence of a TBX22 gene (MIM*300307) defect. Our report suggests CLP as a possible unreported feature and redefines the critical phenotypic regions of 5q14.3 deletion syndrome.

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Non-classical 1p36 deletion in a patient with Duane retraction syndrome: case report and literature review

Molecular Cytogenetics ◽

10.1186/s13039-020-00510-5 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Emiy Yokoyama ◽

Camilo E. Villarroel ◽

Sinhué Diaz ◽

Victoria Del Castillo ◽

Patricia Pérez-Vera ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Deletion Syndrome ◽

Clinical Feature ◽

Facial Dysmorphism ◽

Case Presentation ◽

Ocular Manifestations ◽

Retraction Syndrome ◽

Duane Retraction Syndrome

Abstract Background Monosomy of 1p36 is considered the most common terminal microdeletion syndrome. It is characterized by intellectual disability, growth retardation, seizures, congenital anomalies, and distinctive facial features that are absent when the deletion is proximal, beyond the 1p36.32 region. In patients with proximal deletions, little is known about the associated phenotype, since only a few cases have been reported in the literature. Ocular manifestations in patients with classical 1p36 monosomy are frequent and include strabismus, myopia, hypermetropia, and nystagmus. However, as of today only one patient with 1p36 deletion and Duane retraction syndrome (DRS) has been reported. Case presentation We describe a patient with intellectual disability, facial dysmorphism, and bilateral Duane retraction syndrome (DRS) type 1. Array CGH showed a 7.2 Mb de novo deletion from 1p36.31 to 1p36.21. Discussion Our patient displayed DRS, which is not part of the classical phenotype and is not a common clinical feature in 1p36 deletion syndrome; we hypothesized that this could be associated with the overlapping deletion between the distal and proximal 1p36 regions. DRS is one of the Congenital Cranial Dysinnervation Disorders, and a genetic basis for the syndrome has been extensively reported. The HES3 gene is located at 1p36.31 and could be associated with oculomotor alterations, including DRS, since this gene is involved in the development of the 3rd cranial nerve and the 6th cranial nerve’s nucleus. We propose that oculomotor anomalies, including DRS, could be related to proximal 1p36 deletion, warranting a detailed ophthalmologic evaluation of these patients.

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A Novel 23.1 Mb Interstitial Deletion Involving 7q22.3q32.1 in a Girl with Short Stature, Motor Delay, and Craniofacial Dysmorphism

Cytogenetic and Genome Research ◽

10.1159/000381234 ◽

2015 ◽

Vol 145 (1) ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Maria del Refugio Rivera-Vega ◽

Luis A. Gómez-del Angel ◽

Juan M. Valdes-Miranda ◽

Adrián Pérez-Cabrera ◽

Luz M. Gonzalez-Huerta ◽

...

Keyword(s):

Intellectual Disability ◽

Short Stature ◽

De Novo ◽

Deletion Syndrome ◽

Congenital Defects ◽

Facial Dysmorphism ◽

Motor Delay ◽

Craniofacial Dysmorphism ◽

7Q Deletion ◽

Omim Database

Interstitial deletions of 7q show a wide phenotypic spectrum that varies with respect to the location and size of the deleted region. They lead to craniofacial dysmorphism with intellectual disability, growth retardation, and various congenital defects. Here, a Mexican girl with microcephaly, facial dysmorphism, short stature, hand anomalies, and intellectual disability was analyzed by CytoScan HD array. Her phenotype was associated with a de novo 7q22.3q32.1 deletion involving 109 loci, 57 of them listed in the OMIM database. This novel deletion increases the knowledge of the variability in the rupture sites of the region and expands the spectrum of molecular and clinical defects of the 7q deletion syndrome.

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A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk

BMC Genetics ◽

10.1186/1471-2156-15-24 ◽

2014 ◽

Vol 15 (1) ◽

pp. 24 ◽

Cited By ~ 18

Author(s):

Samuel G Younkin ◽

Robert B Scharpf ◽

Holger Schwender ◽

Margaret M Parker ◽

Alan F Scott ◽

...

Keyword(s):

Cleft Lip ◽

De Novo ◽

Candidate Locus ◽

Genome Wide ◽

A Genome ◽

Cleft Lip Palate ◽

Genome Wide Study

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MED13L-related intellectual disability due to paternal germinal mosaicism

Molecular Case Studies ◽

10.1101/mcs.a006124 ◽

2021 ◽

pp. mcs.a006124

Author(s):

Beata Bessenyei ◽

Istvan Balogh ◽

Attila Mokanszki ◽

Aniko Ujfalusi ◽

Rolph Pfundt ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Mediator Complex ◽

Facial Dysmorphism ◽

Facial Features ◽

Speech Delay ◽

Motor Delay ◽

First Case ◽

Intragenic Deletion ◽

Germinal Mosaicism

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

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De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

10.1101/378349 ◽

2018 ◽

Author(s):

Susan M. Hiatt ◽

Matthew B. Neu ◽

Ryne C. Ramaker ◽

Andrew A. Hardigan ◽

Jeremy W. Prokop ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Small Gtpases ◽

Small Gtpase ◽

Facial Dysmorphism ◽

De Novo Mutations ◽

Binding Region ◽

Gtp Hydrolysis ◽

Genetic Changes ◽

Developmental Problems

AbstractMutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies, but the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins, and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p=4.93 × 10−11) than expected from the estimated mutation rate. Further, all de novo variants described here affect conserved residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. We directly assayed GTP hydrolysis and RALA effector-protein binding, and all but one tested variant significantly reduced both activities. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.Author SummaryWhile many causes of developmental disabilities have been identified, a large number of affected children cannot be diagnosed despite extensive medical testing. Previously unknown genetic factors are likely to be the culprits in many of these cases. Using DNA sequencing, and by sharing information among many doctors and researchers, we have identified a set of individuals with developmental problems who all have changes to the same gene, RALA. The affected individuals all have similar symptoms, including intellectual disability, speech delay (or no speech), and problems with motor skills like walking. In nearly all of these cases (10 of 11), the genetic change found in the child was not inherited from either parent. The locations and biological properties of these changes suggest that they are likely to disrupt the normal functions of RALA and cause significant health problems. We also performed experiments to show that the genetic changes found in these individuals alter two key functions of RALA. Together, we have provided evidence that genetic changes in RALA can cause DD/ID. These results will allow doctors and researchers to identify additional children with the same condition, providing a clinical diagnosis to these families and leading to new research opportunities.

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De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2019.02.023 ◽

2019 ◽

Vol 104 (4) ◽

pp. 758-766 ◽

Cited By ~ 3

Author(s):

Illja J. Diets ◽

Roos van der Donk ◽

Kristina Baltrunaite ◽

Esmé Waanders ◽

Margot R.F. Reijnders ◽

...

Keyword(s):

Intellectual Disability ◽

Short Stature ◽

De Novo ◽

Facial Dysmorphism ◽

Pathogenic Variants

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Aesthetic and Functional Outcome of Surgical and Orthodontic Correction of Bilateral Clefts of Lip, Palate, and Alveolus

The Cleft Palate-Craniofacial Journal ◽

10.1597/1545-1569_1999_036_0407_aafoos_2.3.co_2 ◽

1999 ◽

Vol 36 (5) ◽

pp. 407-412 ◽

Cited By ~ 11

Author(s):

Alexander Gaggl ◽

Günter Schultes ◽

Hans Kärcher

Keyword(s):

Cleft Lip ◽

Functional Results ◽

Model Analysis ◽

Long Term Results ◽

Slight Reduction ◽

Lateral Cephalograms ◽

Bilateral Cleft Lip ◽

Cleft Lip Palate ◽

Maxilla And Mandible

Objective: To assess the aesthetic and functional long-term results of surgical and orthodontic treatment of patients with bilateral cleft lip, palate, and alveolus. Design: Long-term follow-up study. Setting: Teaching hospital in Austria. Patients: Twenty adult patients who had been operated on as children for bilateral cleft lip, palate, and alveolus. Interventions: Lateral cephalometric and model analysis. The sum of all mesiodistal tooth diameters in the maxilla and mandible were compared with standard Bolton tracings. Main outcome measures: Aesthetic and functional results. Results (model analysis): The upper arch was too wide in 12 patients and the mandibular arch was too wide in 4 patients. In 11 patients, the lateral teeth were crowded, and all had a persistent transverse space deficit and a reduction in sagittal measurements. Fifteen patients had alveolar midline displacement of the maxilla as well as of the mandible. Results (lateral cephalometric measurements): The lateral cephalograms showed a mean sella-nasion-A point angle of 77° and a maxillary baseline-nasion-sella line angle of 9°, indicating a tendency toward maxillary retrognathia. An anterior facial height index of 42% (compared with the standard 58%) indicated a slight reduction in midface height with consequent increase in the height of the lower face. Conclusion: There is specific growth impairment of the midface in adults who were treated as children for bilateral clefts of lip, palate, and alveolus. An optimal result can be achieved only by additional orthognathic surgery (Le Fort II osteotomy).

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Cerebral White Matter Lesions and Dysmorphisms: Signs Suggestive of 6p25 Deletion Syndrome—Literature Review

Journal of Pediatric Genetics ◽

10.1055/s-0039-1694015 ◽

2019 ◽

Vol 08 (04) ◽

pp. 205-211

Author(s):

Piero Pavone ◽

Simona Domenica Marino ◽

Giovanni Corsello ◽

Martino Ruggieri ◽

Danilo Castellano Chiodo ◽

...

Keyword(s):

White Matter ◽

Developmental Delay ◽

De Novo ◽

Clinical Manifestations ◽

Deletion Syndrome ◽

Cerebral White Matter ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Perivascular Spaces ◽

Renal Malformations

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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