Chromosome 1q21.1 Duplication Syndrome

A number sign (#) is used with this entry because the phenotype is caused by duplication of one or more genes within the chromosome 1q21.1 region (chr1: 145.0-146.4 Mb, NCBI36). The reciprocal deletion has been identified (612474).

Clinical Features

Among 8 patients with duplication of an approximately 1.35-Mb region of chromosome 1q21.1, identified through a screen of 5,218 patients with unexplained mental retardation, autism, or congenital anomalies, Mefford et al. (2008) observed that 4 of the 8 (50%) had autism or autistic behaviors, consistent with reported 1q21.1 duplication in patients with autism (Autism Genome Project Consortium, 2007). Two patients were initially identified among 141 patients with autism, suggesting even greater enrichment in this population. Other common phenotypic features of the 8 duplication carriers included mild to moderate mental retardation in 5 (62.5%), macrocephaly or relative macrocephaly in 4 (50%), and mild dysmorphic features in 5 (62.5%).

Brunetti-Pierri et al. (2008) identified 17 probands with the 1q21 microduplication syndrome. The microduplication was shown to have been inherited in most cases where parental samples were available for analysis. Affected individuals had normal growth but manifested macrocephaly. The mean frontal occipital circumference (FOC) Z score for the microduplication cases (probands, parents and sibs carrying the microduplication) was 0.95 (95% confidence interval = 0.06; 1.83), which was statistically different from the population mean (1-sample T test, p less than 0.05). Some individuals with the 1q21 microduplication manifested other congenital anomalies, autism, attention deficit-hyperactivity disorder (ADHD), and hypotonia.

Dolcetti et al. (2013) performed a systematic review of 22 studies reporting 107 individuals (59 children and 48 adults) with 1q21.1 duplication and reported on 7 adult cases identified in studies of schizophrenia and tetralogy of Fallot at University of Toronto. Five cases were ascertained as controls, 32 as relatives of probands, and 70 as having clinical features including 15 with autism spectrum disorder (ASD), 12 with congenital heart disease, 10 with schizophrenia, and 33 with other, mostly developmental, features. The 1q21.1 duplication was significantly enriched in the cohorts with schizophrenia (p = 0.0155) and tetralogy of Fallot (p = 0.0040) at the University of Toronto as compared with controls. Besides the presenting features, the most common feature were macrocephaly and abnormalities of possible connective tissue origin (e.g., carpal tunnel syndrome).

Bernier et al. (2016) compared the phenotype of 19 patients with a 1q21.1 deletion (612474) and 19 patients with a 1q21.1 duplication who were ascertained through clinical genetic testing. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. In deletion cases, the most common psychiatric disorders included internalizing disorders, such as mood and anxiety disorders (26%). The most commonly reported nonneurologic medical problems included short stature (50%), cataracts (33%), and cardiac problems (33%). In duplication carriers, the most common psychiatric/developmental disorders included ASD (41%), ADHD (29%), and intellectual disability (29%). The most commonly reported nonneurologic medical problems included scoliosis (36%), short stature (27%), and gastric ulcers (27%). Whereas microcephaly was prevalent in deletion carriers, macrocephaly was common in duplication carriers.

Molecular Genetics

Mefford et al. (2008) identified duplication of chromosome 1q21.1 in 9 children with mental retardation or autism spectrum disorder and other variable features out of a sample of 5,218 patients. The duplication was then identified in 3 additional patients in an independent sample of 788 patients with mental retardation and congenital anomalies. One of the 9 patients with the duplication carried an additional large chromosomal abnormality and was excluded from further analysis. Of the remaining 8 patients with duplication, 2 had inheritance from an unaffected father, 2 had de novo duplication (parent of origin not known), and 4 did not have parental DNA available for analysis. The duplication was found in 1 of 4,737 controls.

Brunetti-Pierri et al. (2008) suggested that the HYDIN paralog located on chromosome 1q21 (HYDIN2; 610813) is a dosage-sensitive gene responsible for the macrocephaly seen in 17 microduplication carriers studied by them. The authors also implicated the HYDIN2 gene in the microcephaly seen in carriers of the reciprocal microdeletion (612474).

To investigate large copy number variants (CNVs) segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence of association of duplication at chromosome 1q21 with autism, mental retardation, and schizophrenia (CNV p = 0.041). They identified 15 duplications in this region; 12 of these were disease-associated.

Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (610543, 613458), and 22q11.2 (192430, 608363). Sahoo et al. (2011) identified 113 individuals with the 1q21.1 duplication; 7 were de novo, 19 maternally inherited, 11 paternally inherited, and 76 were of unknown inheritance. The average age at diagnosis was 8.7 years, with an age range of 0.1 to 38.5 years. The indications for study included developmental delay, autism, failure to thrive, dysmorphic features, seizures, congenital heart disease, polydactyly, and macrocephaly. Sahoo et al. (2011) reported observing the 1q21.1 microduplication in 113 of 23,250 cases sent to their lab. There were 3 carriers of the 1q21.1 microduplication among 5,674 controls for a frequency of 0.02% (Itsara et al., 2009) (p less than 0.0001). This microduplication had not previously been reported in a schizophrenia population, but in a case-control comparison of variable neurodevelopmental deficits was seen in 0.17% of cases versus 0.02% of controls, as reported by Vassos et al. (2010). Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 1q21.1 duplication was identified in 28 cases and 3 controls for a p value of 0.0004 and a frequency of 1 in 562 cases.