Duplication of 19p13.3 in 11-Year-Old Male Patient with Dysmorphic Features and Intellectual Disability: A Review.
ABSTRACT: We present a clinical report of an 11-year-old male patient with an interstitial duplication of 19p13.3 (829?kb in size) at genomic coordinates 3,804,495-4,033,722?bp (hg19) identified by chromosomal microarray analysis and review the literature from nine published reports adding knowledge regarding this chromosomal anomaly and clinical outcomes. The size of the duplication ranged from 0.83 to 8.9 Mb in the nine individuals. The young boy in our report was dysmorphic with microcephaly, abnormal craniofacial features, intellectual disability, aggression, and a heart murmur. All patients were found to have a psychomotor developmental delay and/or intellectual disability with the majority having microcephaly, intrauterine growth retardation, and hypotonia. Common craniofacial findings included a tall, prominent forehead, an elongated face, epicanthal folds, hypertelorism, prominent low-set ears, philtrum anomaly, and a small mouth. Other less common features included abnormal digits, sparse hair, and cardiac defects. Clinical features, chromosome duplication sizes, locations, and the number of genes will be summarized in a tabular form.
Project description:Trisomy 16 is the most common type of autosomal trisomy associated with spontaneous abortion and is incompatible with life. Upon examining previously reported cases of partial chromosome 16q duplication, it was noted that the majority of cases had complex chromosomal abnormalities due to parental balanced chromosomal translocation carriage. The clinical presentation of very rare pure partial trisomy 16q cases was associated with congenital anomalies, facial dysmorphic findings and intellectual disability. In this study, we evaluated the physical characteristics and genetic data of an 8-month-old girl with developmental delay and facial dysmorphic features. Dysmorphic features including prominent metopic suture, synophrys, asymmetric head shape, triangular and asymmetric face, telecanthus, epicanthal folds, down-slanting palpebral fissures, microphthalmia of the left eye, anteverted nares, smooth and tented philtrum, microretrognathia, low-set posteriorly rotated ears, auricular pits, high-arched palate, thin upper lip and hypotonia were recorded. Her karyotype was 46,XX,add(16)(q24). To identify the extension of the duplicated section, array comparative genomic hybridization (aCGH) analysis was performed, which showed a de novo 29.8 Mb duplication [arr[hgl9] 16q12.1q23.3(52459169-82285105) x 3], interpreted to be pathogenic. We present this case report to clarify the clinical findings of a rare chromosomal anomaly, discuss the genes that may be related to the phenotype and advance the literature in terms of knowledge regarding genotypephenotype correlation.
Project description:We report on a girl, born to first-cousin Lebanese parents, with severe intellectual disability, congenital hip luxation, cardiac malformation, short stature, facial dysmorphic features including microcephaly, sparse hair, bilateral epicanthal folds, ataxia, seizures, and elevated lactate and pyruvate levels in serum. Whole exome sequencing was carried out on the patient's DNA. Potentially causal homozygous variants in the MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp) genes were found. The potential pathogenicity of these variants, and the possibility that the 2 variants could synergistically act to produce the phenotype reported, is discussed.
Project description:BACKGROUND: During whole genome microarray-based comparative genomic hybridisation (array CGH) screening of subjects with idiopathic intellectual disability, we identified two unrelated individuals with a similar de novo interstitial microdeletion at 2p15-2p16.1. Both individuals share a similar clinical phenotype including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. METHODS: Clinical assessments, and cytogenetic, array CGH and fluorescence in situ hybridisation (FISH) analyses were performed. RESULTS: The microdeletions discovered in each individual measured 4.5 Mb and 5.7 Mb, spanning the chromosome 2p region from 57.2 to 61.7 Mb and from 56 to 61.7 Mb, respectively. Each deleted clone in this range demonstrated a dosage reduction from two to one copy in each proband except for clone RP11-79K21, which was present in three copies in each proband and in four copies in their respective parents (two per each chromosome 2 homologue). DISCUSSION: The common constellation of features found in the two affected subjects indicates that they have a newly recognised microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 4.5-Mb segment of the 2p15-16.1 region.
Project description:Microdeletions in the 10q26.1 region are related to intellectual disability, growth delay, microcephaly, distinctive craniofacial features, cardiac defects, genital abnormalities and inner ear abnormalities. The genes responsible for inner ear abnormalities have been narrowed to fibroblast growth factor receptor 2 gene (FGFR2), H6 family homeobox 2 gene (HMX2) and H6 family homeobox 3 gene (HMX3). An additional patient with distinctive craniofacial features, congenital deafness and balance dysfunctions showed a de novo microdeletion of 10q26.11q26.13, indicating the existence of a gene responsible for inner ear abnormalities in this region.
Project description:Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.
Project description:BACKGROUND:Homozygous mutations and deletions of the microcephalin gene (MCPH1; OMIM *607117) have been identified as a cause of autosomal recessive primary microcephaly and intellectual disability (MIM #251200). Previous studies in families of Asian descent suggest that the severity of the phenotype may vary based on the extent of the genomic alteration. We report chromosome microarray (CMA) findings and the first described family study of a patient with primary microcephaly in a consanguineous Hispanic family. CASE PRESENTATION:The proband, a boy born at full-term to consanguineous parents from Mexico, presented at 35 months of age with microcephaly, abnormal brain MRI findings, underdeveloped right lung, almond-shaped eyes, epicanthal folds, bilateral esotropia, low hairline, large ears, smooth philtrum, thin upper lip, and developmental delay. MRI of the brain showed a small dermoid or lipoma (without mass effect) within the interpeduncular cistern and prominent arachnoid granulation. The underdeveloped right lung was managed with long-acting inhaled corticosteroids. Otherwise the proband did not have any other significant medical history. The proband had 2 older brothers, ages 14 and 16, from the same consanguineous parents. The 14-year-old brother had a phenotype similar to that of the proband, while both parents and the oldest brother did not have the same phenotypic findings as the proband. The SNP-based CMA analysis of the proband detected a homozygous 250-kb microdeletion at 8p23.2p23.1, extending from 6,061,169 to 6,310,738 bp [hg19]. This genomic alteration encompasses the first 8 exons of MCPH1. Follow-up studies detected the same homozygous deletion in the affected brother, segregating with microcephaly and intellectual disability. Regions of homozygosity (ROHs) were also observed in the affected brother. Since ROHs are associated with an increased risk for recessive disorders, presence of ROH may also contribute to the phenotype of the affected brothers. The parents were both hemizygous for the deletion. CONCLUSION:Here we report a homozygous deletion of multiple exons of the MCPH1 gene that was associated with primary microcephaly and intellectual disability in a Hispanic family. In the context of previous studies, our results support the idea that deletions involving multiple exons cause a more severe phenotype than point mutations.
Project description:Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113?Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
Project description:3q26.33-3q27.2 microdeletion can be classified as a clinical entity characterized by intrauterine growth retardation, feeding problems in infancy, short stature, intellectual disability, hypotonia, dysmorphic facial features (medially sparse eyebrows, narrow horizontal palpebral fissures, epicanthal folds, flat nasal bridge and tip, short philtrum, and downturned corners of mouth), and teeth and feet abnormalities.
Project description:BACKGROUND:1q21 microdeletion syndrome is a rare contiguous gene deletion disorder with de novo or autosomal dominant inheritance patterns and its phenotypic features include intellectual disability, distinctive facial dysmorphism, microcephaly, cardiac abnormalities, and cataracts. MECP2 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by intellectual disability, global developmental delay, and other neurological complications including late-onset seizures. Previously, these two different genetic syndromes have not been reported segregating independently in a same family. CASE PRESENTATION:Here we describe two siblings carrying either a chromosome 1q21 microdeletion or a chromosome Xq28 duplication. Using a comparative genomic hybridization (CGH) array, we identified a 1.24 Mb heterozygous deletion at 1q21 resulting in the loss of 9 genes in a girl with learning disability, hypothyroidism, short stature, sensory integration disorder, and soft dysmorphic features including cupped ears and a unilateral ear pit. We also characterized a 508 kb Xq28 duplication encompassing MECP2 in her younger brother with hypotonia, poor speech, cognitive and motor impairment. The parental CGH and quantitative PCR (qPCR) analyses revealed that the 1q21 deletion in the elder sister is de novo, but the Xq28 duplication in the younger brother was originally inherited from the maternal grandmother through the mother, both of whom are asymptomatic carriers. RT-qPCR assays revealed that the affected brother has almost double the amount of MECP2 mRNA expression compared to other family members of both genders including maternal grandmother and mother who have the same Xq28 duplication with no phenotype. This suggests the X chromosome with an Xq28 duplication in the carrier females is preferentially silenced. CONCLUSION:From our understanding, this would be the first report showing the independent segregation of two genetically unrelated syndromes, 1q21 microdeletion and Xq28 duplication, in a same family, especially in siblings. Although these two chromosomal abnormalities share some similar phenotypes such as intellectual disability, mild dysmorphic features, and cardiac abnormalities, the presence of two unrelated and rare syndromes in siblings is very unusual. Therefore, further comprehensive investigations in similar cases are required for future studies.
Project description:Recurrent reciprocal 1q21.1 deletions and duplications have been associated with variable phenotypes. Phenotypic features described in association with 1q21.1 microdeletions include developmental delay, craniofacial dysmorphism and congenital anomalies. The 1q21.1 reciprocal duplication has been associated with macrocephaly or relative macrocephaly, frontal bossing, hypertelorism, developmental delay, intellectual disability and autism spectrum disorder.Our study describes seven patients, who were referred to us for developmental delay/intellectual disability, dysmorphic features and, in some cases, congenital anomalies, in whom we identified 1q21.1 CNVs by array-CGH.Our data confirm the extreme phenotypic variability associated with 1q21.1 microdeletion and microduplication. We observed common phenotypic features, described in previous studies, but we also described, for the first time, congenital hypothyroidism in association with 1q21.1 deletion and trigonocephaly associated with 1q21.1 duplication.The aim of this study is to contribute to the definition of the phenotype associated with reciprocal 1q21.1 deletions and duplications.