ClinVar Genomic variation as it relates to human health

In 2 brothers with the renal-coloboma syndrome (120330) reported by Weaver et al. (1988), Sanyanusin et al. (1995) found insertion of a G at position 619 (619insG) of the PAX2 gene (codon 26) resulting in a frameshift and predicted to result in a truncated PAX2 protein due to introduction of a termination codon 26 amino acids downstream from the mutation. The mutation probably resulted in haploinsufficiency of PAX2. The mutation was not present in the mother; the father was not available for study. Schimmenti et al. (1997) noted that previously reported patients with renal-coloboma syndrome had ocular and/or renal abnormalities, but PAX2 expression patterns suggested that auditory and CNS abnormalities may be additional features of the condition. To determine whether additional clinical features are associated with PAX2 mutations, they used PCR-SSCP to identify PAX2 gene mutations in patients with a variety of abnormalities. They detected a 1-bp insertion (G) in exon 2 of the PAX2 gene in 3 patients from 2 different families. The insertion occurred in a sequence of 7 G's, a sequence that appears to be particularly prone to mutation through slippage during DNA replication. Their patient 657 was a 25-year-old male who was moderately mentally retarded and microcephalic. At age 3 months, he presented with esotropia, exophthalmos, and lack of direct pupillary response to light stimulation of the left eye. The anterior segment of both eyes was normal. The fundi of both eyes were lightly pigmented. In the left eye, no optic nerve head and no retinal vessels were present. In the area where the disc is normally present, a gray structure with an overlying pit was evident. In the right eye, milder changes were observed, including a hypoplastic optic disc with a pit surrounded by pigment, diffuse atrophic changes of the retina, and retinochoroidal colobomas in the inferior fundus. Electroretinography was subnormal in the right eye; responses were electronegative in the left eye. At age 7 years, ultrasound and CT scans showed a retrobulbar cyst behind the left microphthalmic eye. At age 4 months, renal insufficiency was noted with hypoplastic kidneys. The patient's mother, a 48-year-old woman, had hypertension and proteinuria during 2 pregnancies at ages 19 and 22 years. End-stage renal disease and bilateral renal hypoplasia were diagnosed at age 24 years, and she was maintained on hemodialysis waiting for a second renal transplant after failure of her first transplant. Bilateral opacities of the anterior and posterior lens capsules were noted and required surgical treatment. Fundi showed hypoplastic optic discs bilaterally. Visual acuity was 20/30 in both eyes. She had normal intelligence, normal hearing, and no history of seizures. Physical examination was significant for soft skin, which was also noted in her son. The third patient was a 20-year-old female who had developed proteinuria at age 3 years and progressed to end-stage renal disease. Renal biopsy at age 10 years showed focal segmental glomerulosclerosis and renal ultrasound showed small kidneys. Renal transplant from her brother at age 18 years was rejected and the patient was maintained on hemodialysis awaiting a cadaveric transplant. Bilateral optic nerve colobomas were discovered at the age of 6 years. At age 20, she had 'relatively good vision' and did not require corrective lenses. Bilateral inguinal hernias had been repaired at age 6 years. Tellier et al. (1998) demonstrated that this relatively frequent and recurrent mutation can produce either isolated renal hypoplasia or renal hypoplasia associated with microphthalmia and retinal degeneration. The same mutation is responsible for the Pax2 1Neu mutant, a mouse model for human RCS. Amiel et al. (2000) described a family in which 3 sibs had renal-coloboma syndrome and the PAX2 619insG mutation. The unaffected parents did not carry the mutation, suggesting the presence of germline mosaicism. The study of a PAX2 intragenic DNA microsatellite marker showed that the mutation was of paternal origin (false paternity was excluded by the study of polymorphic markers). In a family in which at least 7 members had renal-coloboma syndrome, Ford et al. (2001) identified the 619insG frameshift mutation in all of those affected. The authors noted remarkable variability in both the ocular and renal manifestations. Bower et al. (2012) reviewed published cases of PAX2 mutations as well as data from a consortium of 3 laboratories and stated that the 619insG mutation, which they designated 76dup (Val26Cysfs*28), was the most common recurrent mutation. Their nucleotide numbering reflected the cDNA transcript with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence. (less)

Abnormality of the optic nerve (present) , Myopia (present) , Vertigo (present) , Tinnitus (present) , Abnormality of urine homeostasis (present) , Abnormality of reproductive system physiology (present) , Abnormal renal morphology (present) , Abnormal renal physiology (present) (less)