Chromosome 1q21.1 Deletion Syndrome, 1.35-Mb

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr1: 145.0-146.4 Mb, NCBI36).

See 274000 for another contiguous gene deletion syndrome, thrombocytopenia-absent radius (TAR) syndrome, that maps to a nonoverlapping region of chromosome 1q21.1.

Clinical Features

Among 21 patients with a 1.35-Mb deletion in chromosome 1q21.1, Mefford et al. (2008) found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild to moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The majority of persons with the deletion had a history of mild to moderate developmental delay (16 of 21, 76.2%) and dysmorphic features (17 of 21, 81%), consistent with their ascertainment criteria. Three parents were also mildly affected; however, 5 probands had normal cognitive development, and 4 apparently unaffected parents had the same deletion. In addition, 14 of the 21 patients (66.7%) and 2 parents with the deletion had microcephaly or relative microcephaly. Other phenotypic features noted in more than 1 patient with deletion included ligamentous laxity or joint hypermobility in 5, congenital heart abnormality in 6, hypotonia in 5, seizures in 3, and cataracts in 3. Facial anomalies were quite variable and generally mild. There were no notable phenotypic differences among carriers of a deletion with different breakpoints. Interestingly, this same deletion was recently described in an adult patient with schizophrenia (Walsh et al., 2008). Mefford et al. (2008) mapped the breakpoint in this patient and found it to be identical to that found in their sample of patients. Mefford et al. (2008) noted that they found this deletion in 0.5% of patients with developmental abnormalities studied.

Brunetti-Pierri et al. (2008) reported an additional 21 probands with a 1q21 microdeletion. Fifteen had the 1.35-Mb deletion and an additional 6 had a deletion involving the 1.35 and the TAR critical region, extending to a total of about 2 Mb (274000). The majority of microdeletions were inherited, and incomplete penetrance was noted. Among the probands and their affected parents microcephaly was described in the majority. The mean frontal occipital circumference (FOC) Z score for microdeletion cases (probands, parents, and sibs carrying the microdeletion) was -2.53 (95% confidence interval = -2.96; -2.11). Statistical analysis of probands only yielded a Z score of -2.55 (95% CI -3.12; -1.98). The authors noted that macrocephaly is seen in the majority of patients with the reciprocal microduplication (612475). Patients with 1q21 microdeletion had frontal bossing, deep-set eyes, and bulbous nose as the most frequent dysmorphic facial features. Numerous other congenital anomalies were detected in some, but not all, cases. Attention deficit-hyperactivity disorder (ADHD), aggressive behavior, and seizure disorders were identified in some. Many of the patients were too young to have full cognitive and behavioral abnormalities identified. Learning disabilities were reported in several of the affected parents.

Bernier et al. (2016) compared the phenotype of 19 patients with a 1q21.1 deletion and 19 patients with a 1q21.1 duplication (612475) 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 autism spectrum disorder (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

By screening 5,218 patients with unexplained mental retardation, autism, or congenital anomalies for the presence of microdeletions or microduplications in chromosome 1q21.1, Mefford et al. (2008) identified 25 individuals with a recurrent 1.35-Mb deletion. Of the 21 probands without secondary karyotype abnormalities, the 1q21.1 deletion was de novo in 7 (3 with maternal origin, 1 with paternal origin, and 3 with undetermined parental origin), maternally inherited in 3, paternally inherited in 4, and of unknown inheritance (because the parents were unavailable for study) in 7. Three parents with the deletion were apparently unaffected, and 4 were mildly affected. The deletion was absent in a series of 4,737 control persons (p = 1.1 x 10(-7)). This same deletion was identified in 3 individuals from an independent sample of 788 patients with mental retardation and congenital anomalies. The minimally deleted region spans approximately 1.35 Mb on chromosome 1, 143.65 to 145 Mb (according to NCBI build 35), or 145 to 146.35 Mb (according to NCBI build 36) and includes at least 7 genes. The reciprocal duplication (612475) was present in 9 children with mental retardation or autism spectrum disorder (ASD) and other variable features (p = 0.02). Because mutations in the GJA5 (121013) and GJA8 (600897) genes cause cardiac and eye phenotypes, respectively, Mefford et al. (2008) sequenced the remaining alleles of these genes in deletion carriers, but found no mutations. There was no significant difference in epigenetic markings between affected and unaffected deletion carriers. This deletion had been reported in patients with isolated heart defects (Christiansen et al., 2004), cataracts (Redon et al., 2006), mullerian aplasia (Cheroki et al., 2008), autism (Autism Genome Project Consortium, 2007), and schizophrenia (Stefansson et al., 2008, International Schizophrenia Consortium, 2008, and Walsh et al., 2008). Mefford et al. (2008) stated that, while they identified several unaffected deletion carriers, it is possible that apparently unaffected parents who have a 1q21 deletion could have subtle phenotypic features consistent with the deletion that would become evident on further clinical evaluation. In one of their patients subtle cataracts and patent ductus arteriosus were detected only after directive studies were performed upon discovery of the 1q21 deletion.

Brunetti-Pierri et al. (2008) suggested that the HYDIN paralog located in the 1q21 interval (HYDIN2; 610813) is a dosage-sensitive gene and that deletion of 1 copy is responsible for the microcephaly seen in their group of 21 probands with a 1q21 microdeletion. The HYDIN2 gene is exclusively expressed in brain.

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 to support the association of deletion in chromosome 1q21 with autism and schizophrenia (CNV p = 1.67 x 10(-4)). They identified 27 CNVs in this region; 24 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 (612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (610543, 613458), and 22q11.2 (192430, 608363). Sahoo et al. (2011) identified 18 individuals with a 1q21.1 deletion; 12 were de novo, 18 maternally inherited, 15 paternally inherited, and 73 of unknown inheritance. The average age at diagnosis was 7.5 years with an age range of 0.2 to 41 years, and the indications for study included developmental delay, autism, failure to thrive, dysmorphic features, seizures, congenital heart disease, polydactyly, and macrocephaly. Sahoo et al. (2011) studied 107 1q21.1 microdeletion patients among 23,250 cases referred to their laboratory for an incidence of 0.46%, compared with 3 in 5,674 controls, reported by Itsara et al. (2009) (p = less than 0.0001). A previously reported case-control comparison in schizophrenia populations observed a frequency of 0.2% versus 0.023% (Kirov et al., 2009). The frequency reported in a case-control comparison in a variable neurodevelopmental deficit population was 0.47%, similar to that seen in the population of Sahoo et al. (2011), with a control frequency of 0.0% (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 implied 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 deletion was identified in 55 cases and 3 controls for a p value of 5.38 x 10(-9) and a frequency of 1 in 286 cases.

Dumas et al. (2012) used specialized bioinformatics tools developed for scoring highly duplicated DUF1220 sequences to implement targeted 1q21 array comparative genomic hybridization on 42 individuals with 1q21-associated microcephaly and macrocephaly. Dumas et al. (2012) showed that of 53 genes in the 1q21 region examined, those with DUF1220 sequences showed the strongest association with brain size among individuals with 1q21-associated microcephaly, particularly with respect to the 3 evolutionarily conserved DUF1220 clades CON1 (p = 0.0079), CON2 (p = 0.0134), and CON3 (p = 0.0116). Interestingly, all 1q21 DUF1220-encoding genes belonging to the NBPF family (e.g., 610414) showed significant correlations with frontal-occipital circumference Z scores in the deletion group. In a similar survey of a nondisease population, Dumas et al. (2012) showed that DUF1220 copy number exhibited the strongest correlation with brain gray matter volume (CON1, p = 0.0246 and CON2, p = 0.0334). Notably, only DUF1220 sequences were consistently significant in both disease and nondisease populations. Dumas et al. (2012) concluded that taken together, their data strongly implicated the loss of DUF1220 copy number in the etiology of 1q21-associated microcephaly and supported the view that DUF1220 domains function as general effectors of evolutionary, pathological, and normal variation in brain size.