Array‐CGH defined chromosome 1p duplication in a patient with autism spectrum disorder, mild mental deficiency, and minor dysmorphic features

Abstract

Array comparative genomic hybridization (array CGH) has recently lead to the characterization of many novel microdeletion and microduplication syndromes; it has revolutionized the genetic testing available for patients with learning disabilities, who have the ''chromosomal phenotype'' with dysmorphic features and multiple anomalies [Slavotinek, 2008]. Chromosome duplications involving 1p are rarely reported (fewer than 20 patients in the literature) and a distinct phenotype has yet to be defined; patients appear to have short survival, as well as impaired development and congenital malformations, such as congenital heart defects [Lennon et al., 2006]. Among the reported duplicated 1p cases, the variable phenotypic expressivity likely reflects the variation of the duplicated 1p segments.Here we report on a case of duplication of 1p with novel phenotypic and developmental features. During the pregnancy there were threats of miscarriage. He was born at 40 weeks gestation by a normal vaginal delivery with APGAR scores of 9 and 10. Birth weight was 2,950 g (10th-25th centile), length was 50 cm (25th-50th centile), and occipitofrontal head circumference was 34.7 cm (25th-50th centile). Walking independently occurred when he was 1 year old. Since the first year of life, he had difficulty with establishing relationships, as well as psychomotor and language retardation. Astigmatism was diagnosed at 4 years. At 5 years he had a reduction in growth parameters, so the following tests were performed, with normal results: anti-gliadin IgA and IgG, antiendomysium IgA and IgG, free and total T4, T3, TSH, and allergy skin prick testing. Additional normal studies included mutation analysis of the FMR1 gene and urine amino acids, organic acids, and reducing substances. Abdominal ultrasonography showed slight hepatosplenomegaly. EEG during sleep and awake was unremarkable, and IQ was 50. Karyotype was 46,XY; left-hand bone age was 17, according to the Tanner-Whitehouse 2 standards. His family history was negative for mental retardation, behavior anomalies, or birth defects; his parents were nonconsanguineous.He was first evaluated by us at age 17 years. Physical exam showed the following: scant adipose tissue, narrow forehead, small receding chin, prominent nasal bridge, flat nose, short philtrum, midface hypoplasia (Fig. 1), arachnodactyly of the fingers (Fig. 2), and fingers and toes with joint hyperlaxity. A left-hand bone age was equivalent to his chronological age. He had stereotyped movements, such as finger snapping and repeated mannerisms with obsessive-compulsive behavior; his full-scale IQ was 64, with a range between 56 (performance IQ) and 76 (verbal IQ). The psychological profile was compatible with an autism spectrum disorder with mild mental deficiency, based on the Autism Diagnostic Observation Schedule (ADOS) module 4. A brain MRI scan was normal.An array-CGH analysis was performed according to the manufacturer's instructions: DNA of the proband and a control were extracted with a Puregene DNA Isolation Kit (Gentra ...

Array-CGH analysis in Rwandan patients presenting development delay/intellectual disability with multiple congenital anomalies

“…Chromosome 1p duplication is a very rare rearrangement with a variety of clinical features and is associated with short-term survival. To date, only 20 patients have been described in the literature [36]. Due to the high number of genes, approximately 600 genes are included in the duplication region, it was difficult to correlate the genotype to the phenotype.…”

Association of new deletion/duplication region at chromosome 1p21 with intellectual disability, severe speech deficit and autism spectrum disorder-like behavior: an all-in approach to solving the DPYD enigma

“…They vary considerably in size and position on 1p and no distinct phenotype has been defined to date for any duplicated segments on 1p. In addition, most previous cases did not have molecular characterization of duplicated segments, so it was not possible to estimate a region of overlap, or genotype-phenotype correlations [reviewed in 13 ].…”

A rigorous in silico genomic interrogation at 1p13.3 reveals 16 autosomal dominant candidate genes in syndromic neurodevelopmental disorders

“…Subjects with CNVs within the proximal short arm of chromosome 1, specifically in the 1p13.3 region, are rare, and only seven cases have been reported so far ( Tabata et al, 1991 ; Mattia et al, 1992 ; Lo et al, 1998 ; Utkus et al, 1999 ; Bisgaard et al, 2007 ; van Kuilenburg et al, 2009 ; Piccione et al, 2010 ). Importantly, these seven subjects share an overlapping phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, and craniofacial anomalies (CFA) (Cases 1–7), suggesting the presence of syndromic NDD disease genes within 1p13.3.…”

“…CNV cases from the DECIPHER database are denoted by a six-digit reference number. The sizes of the deleted and duplicated regions from Bisgaard et al (2007) (Case 1), van Kuilenburg et al (2009) (Case 2), Piccione et al (2010) (Case 3), and 22 DECIPHER cases are presented relative to our four subjects. Vertical dotted red lines flanking gray background represent the refined four candidate gene loci; 59 genes located within the 4.6 Mb genomic region at 1p13.3 are depicted either in red for positional candidate genes, blue for functional candidate genes, or gray for the remaining genes.…”