Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects1, developmental delay2,3, schizophrenia and related psychoses4,5. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with micro-deletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus6 was inserted into the 1q21.1 region during the evolution of Homo sapiens7; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity.

Although recessive mutations in the anion transporter gene SLC26A4 are known to be responsible for Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA), also known as "DFNB4," a large percentage of patients with this phenotype lack mutations in the SLC26A4 coding region in one or both alleles. We have identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1, a transcriptional activator of SLC26A4. In nine patients with PS or nonsyndromic EVA, a novel c.-103T-->C mutation in this regulatory element interferes with FOXI1 binding and completely abolishes FOXI1-mediated transcriptional activation. We have also identified six patients with mutations in FOXI1 that compromise its ability to activate SLC26A4 transcription. In one family, the EVA phenotype segregates in a double-heterozygous mode in the affected individual who carries single mutations in both SLC26A4 and FOXI1. This finding is consistent with our observation that EVA occurs in the Slc26a4(+/-); Foxi1(+/-) double-heterozygous mouse mutant. These results support a novel dosage-dependent model for the molecular pathogenesis of PS and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery.

Mutations in the Cx26 gene have been shown to cause autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB1 locus on chromosome 13q12. Using direct sequencing, we screened the Cx26 coding region of affected and nonaffected members from seven ARNSHL families either linked to the DFNB1 locus or in which the ARNSHL phenotype cosegregated with markers from chromosome 13q12. Cx26 mutations were found in six of the seven families and included two previously described mutations (W24X and W77X) and two novel Cx26 mutations: a single base pair deletion of nucleotide 35 resulting in a frameshift and a C‐to‐T substitution at nucleotide 370 resulting in a premature stop codon (Q124X). We have developed and optimized allele‐specific PCR primers for each of the four mutations to rapidly determine carrier and noncarrier status within families. We also have developed a single stranded conformational polymorphism (SSCP) assay which covers the entire Cx26 coding region. This assay can be used to screen individuals with nonsyndromic hearing loss for mutations in the CX26 gene. Hum Mutat 11:387–394, 1998. © 1998 Wiley‐Liss, Inc.