Renal‐coloboma syndrome: Prenatal detection and clinical spectrum in a large family

Renal‐coloboma syndrome includes abnormalities in the urogenital and ocular systems as its primary manifestations, although it can be associated with abnormalities in other systems as well. This syndrome is caused by mutations in the PAX2 gene and is transmitted as an autosomal dominant trait. We report a family in which at least 7 members have manifestations of renal‐coloboma syndrome, including two in whom renal disease was diagnosed prenatally by ultrasound examination. A pathogenic frame‐shift mutation (619insG) was found in the PAX2 gene in affected family members, who show remarkable variability in both the ocular and renal manifestations of the syndrome. © 2001 Wiley‐Liss, Inc.     

Different ocular abnormalities in individuals of a three-generation family caused by a new nonsense mutation in the PST domain of the PAX6 gene. Mutations in brief no. 189. Online

PAX6 is a candidate gene for familial aniridia. We have carried out a mutational analysis of the PAX6 gene in a three-generation family from Germany, containing 5 individuals affected with ocular abnormalities. In all affected individuals, a heterozygous mutation was detected in the PAX6 gene, exchanging tyrosine 369 by a stop codon. The mutation is located in the 3' moiety of the PST domain, at the C terminus of the PAX6 protein. In the affected family members, the same heterozygous mutation leads to distinct phenotypes of varying severity. Most notably, no aniridia was observed in one of the family members carrying the mutation, although other ocular abnormalities (underdeveloped iris and cataracts) were present. We discuss the possibility that small C terminal truncations of the PAX6 protein might lead to less severe or more divergent phenotypes than trancations at internal positions.     

Different ocular abnormalities in individuals of a three-generation family caused by a new nonsense mutation in the PST domain of the PAX6 gene

PAX6 is a candidate gene for familial aniridia. We have carried out a mutational analysis of the PAX6 gene in a three-generation family from Germany, containing 5 individuals affected with ocular abnormalities. In all affected individuals, a heterozygous mutation was detected in the PAX6 gene, exchanging tyrosine 369 by a stop codon. The mutation is located in the 3′ moiety of the PST domain, at the C terminus of the PAX6 protein. In the affected family members, the same heterozygous mutation leads to distinct phenotypes of varying severity. Most notably, s of varying severity. Most notably, no aniridia was observed in one of the family members carrying the mutation, although other ocular abnormalities (underdeveloped iris and cataracts) were present. We discuss the possibility that small C terminal truncations of the PAX6 protein might lead to less severe or more divergent phenotypes than truncations at internal positions. © 1998 Wiley-Liss, Inc.     

Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.     

PAX2 gene mutations in pediatric and young adult transplant recipients: kidney and urinary tract malformations without ocular anomalies

Heterozygous humans for PAX2 mutations show autosomal dominant papillorenal syndrome (PRS), consisting of ocular colobomas, renal hypo/dysplasia and progressive renal failure in childhood. PAX2 mutations have also been identified in patients with isolated renal hypo/dysplasia. Twenty unrelated children and young adults with kidney and urinary tract malformations and no ocular abnormalities were retrospectively recruited for PAX2 mutational analysis. All patients had undergone renal transplantation after end-stage renal disease. We identified two new sequence variations: (i) a deletion causing a frameshift (c.69delC) and (ii) a nucleotide substitution determining a splice site mutation (c.410+5 G/A) by predictive analysis. Therefore, we suggest PAX2 molecular analysis to be extended to all patients with congenital malformations of kidney and urinary tract (CAKUT).     

Expression of the PAX2 gene in human embryos and exclusion in the CHARGE syndrome

The CHARGE syndrome comprises ocular coloboma, heart malformation, choanal atresia, retarded growth and development, central nervous system malformations, genital hypoplasia, ear abnormalities, or deafness. The cause of the CHARGE syndrome remains unknown. In the present study, we analyzed the distribution pattern of the PAX2 gene in human embryos and found that PAX2 gene expression occurs in the primordia affected in the CHARGE syndrome. These data prompted us to consider the PAX2 gene a candidate gene in the CHARGE "association." We analyzed the PAX2 gene in 34 patients fulfilling the diagnostic criteria of the CHARGE syndrome for deletion and nucleotidic variations of the coding sequence and identified only polymorphisms. Our data suggest that mutation of the PAX2 gene is not a cause of the CHARGE association. However, the pattern of expression of PAX2 suggests that genes encoding downstream targets effectors could be candidate genes for the CHARGE syndrome.     

Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations

Optic nerve coloboma combined with renal disease, also called renal-coloboma syndrome ( # 120330 in McKusick's Mendelian Inheritance in Man Online, OMIM), a relatively recently characterized syndrome, results from autosomal dominant mutations in the PAX2 gene. Although renal-coloboma syndrome involves both ocular and renal anomalies, some patients are affected with vesico-ureteral reflux (VUR), high frequency hearing loss, central nervous system (CNS) anomalies, and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development. We review here the clinical features of patients with renal-coloboma syndrome and PAX2 mutation. We also review the PAX2 mutations that have been reported to date, and discuss the possible effect of PAX2 mutations on normal development.     

A novel interstitial deletion of 10q24.2q24.32 in a patient with renal coloboma syndrome

Renal coloboma syndrome (RCS) is considered to be a rare autosomal dominant inherited disorder characterized by renal malformations and optic disc coloboma. Ocular anomalies range from asymptomatic abnormalities in retinal blood vessel patterning to large excavations of the optic nerve associated with reduced visual acuity. Commonly observed manifestations of the kidney are renal hypoplasia and vesicoureteric reflux leading to end-stage renal disease. Mutations in the PAX2 gene on chromosome 10 have been identified in patients with RCS. Up to date, nucleotide substitutions, insertions, small deletions, one de novo translocation, and one 240 kb deletion of the coding region of the PAX2 gene have been described to be responsible for RCS.We report here a new case of a patient with RCS due to a deletion of 3.8 Mb on chromosome 10q. Deletions on the long arm of chromosome 10 harboring the PAX2 gene seem to be a rare cause for RCS. Nevertheless, array-CGH testing should represent an important and valuable addition to PAX2 gene sequencing in diagnostic of RCS.     

Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia

Ocular (uveoretinal) colobomas occur in one in 10,000 individuals and present a substantive cause of congenital poor vision. The genetic bases of most forms of uveoretinal coloboma are elusive; mutations in PAX2 are found in only a few cases of coloboma of the retina and optic nerve that occur with renal anomalies as part of the renal-coloboma syndrome (MIM#120330; #167409). From experimental data that upstream expression of sonic hedgehog (SHH) controls Pax2 expression in mice and zebrafish, and from clinical experience that colobomas are observed frequently in patients with holoprosencephaly, we hypothesized that SHH could be a candidate for non-syndromic ocular colobomas (NSOC). We identified a three-generation family in which both a proband and his mother presented with iris and uveoretinal colobomas without optic nerve involvement. A novel 24 bp deletion in the gene SHH was identified in these affected family members, and cosegregated with the phenotype. This is the first report of the association of SHH mutations and uveoretinal coloboma.     

Craniofacial-deafness-hand syndrome revisited

In 1983 Sommer described a new syndrome in a mother and her infant daughter which was subsequently called the syndrome of craniofacial, hand anomalies and sensorineural deafness. The syndrome consisted of a normal calvarium with a flat facial profile, hypertelorism and small palpebral fissures with an antimongoloid slant, a depressed nasal bridge with a button tip and slitlike nares and a small "pursed" mouth. Profound sensorineural hearing loss and ulnar deviation of the hands with flexion contractures of digits three, four and five was evident. The family had another child, a son, two years after the birth of the index case that had the exact manifestations as his mother and sister. Because of three affected family members in two generations and a phenotype of midfacial anomalies and dystopia canthorum resembling Waardenburg syndrome, a search for mutations in the PAX3 gene was undertaken. A missense mutation in the paired domain of PAX3 (Asn47Lys) was detected. We have provided a 20-year follow-up of a syndrome characterized by craniofacial anomalies, hearing loss and hand deformities and which is caused by a PAX3 missense mutation.     

Further delineation of the acro-renal-ocular syndrome

A triad of acral, renal, and ocular abnormalities was reported previously in four families. We report on a fifth family, in which a mother, one of her four sons and one of her two daughters are affected. Major findings in the acro-renal-ocular syndrome are upper limb abnormalities, mainly thumb hypoplasia, eye abnormalities such as coloboma and Duane anomaly and renal migration defects. A close embryological-temporal relationship between the traits of this entity suggest a common monogenic cause. The pattern of inheritance is probably autosomal dominant. Because of a wide variability of clinical manifestations, recognition of the syndrome in individual cases may be difficult. © 1996 Wiley-Liss, Inc.     

PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism

The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant disorder caused by PAX2 gene mutations. We screened the entire coding sequence of the PAX2 gene for mutations in nine patients with RCS. We found five heterozygous PAX2 gene mutations: a dinucleotide insertion (2G) at position 619 in one sporadic RCS case, a single nucleotide insertion (619 + G) in three unrelated cases, and a single nucleotide deletion in a familial case. In this familial case, three affected sibs showed a striking ocular phenotypic variability. Each of the sibs carried a 619insG mutation, whilst unaffected parents did not, suggesting the presence of germline mosaicism. Interestingly, the 619insG mutation has been previously reported in several patients and is also responsible for the Pax21Neu mouse mutant, an animal model of human RCS. This study confirms the critical role of the PAX2 gene in human renal and ocular development. In addition, it emphasises the high variability of ocular defects associated with PAX2 mutations ranging from subtle optic disc anomalies to microphthalmia. Finally, the presence of PAX2 germline mosaicism highlights the difficulties associated with genetic counselling for PAX2 mutations.     

Absence of PAX2 gene mutations in patients with primary familial vesicoureteric reflux.

Vesicoureteric reflux (VUR) is a common childhood condition characterised by regurgitation of urine from the bladder to the kidney. It is the commonest cause of end stage renal failure in children and an important cause in adults. Primary VUR is often familial, suggesting that genetic factors play an important role in its aetiology. Recently, VUR was observed as part of a syndrome, involving optic nerve colobomas and renal anomalies, caused by mutations of the PAX2 gene. PAX2 is a member of the paired box family of genes and is expressed in the ureteric bud and differentiating nephrogenic mesenchyme of the developing kidney. PAX2 has been shown to play a critical role in the development of both the kidney and the ureter. The occurrence of VUR in one family with the PAX2 mutation, and the expression pattern of PAX2 in developing ureteric bud, strongly suggested that PAX2 could be the cause of primary familial VUR. Single strand conformational polymorphism (SSCP) analysis of 23 affected subjects in eight families with primary familial VUR showed no alterations in exons 2-5 of the PAX2 gene. In addition, a polymorphic dinucleotide repeat marker located within the PAX2 gene segregated independently of the disease trait in one large family who primarily had VUR or reflux nephropathy. These results suggest that PAX2 is not a major cause of primary familial reflux.     

Renal coloboma syndrome

Renal coloboma syndrome (RCS), also called papillorenal syndrome, is an autosomal dominant condition characterized by optic nerve dysplasia and renal hypodysplasia. The eye anomalies consist of a wide and sometimes excavated dysplastic optic disc with the emergence of the retinal vessels from the periphery of the disc, frequently called optic nerve coloboma or morning glory anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst and pigmentary macular dysplasia. The kidney abnormalities consist of small and abnormally formed kidneys known as renal hypodysplasia. Histologically, kidneys exhibit fewer than the normal number of glomeruli and these glomeruli are enlarged, a finding called oligomeganephronia. Consequences of the ocular malformations include decreased visual acuity and retinal detachment. Consequences of the renal hypodysplasia include hypertension, proteinuria and renal insufficiency that frequently progresses to end-stage kidney disease. High frequency hearing loss has been reported. Autosomal dominant mutations in PAX2 can be identified in nearly half of all patients with clinical findings suggestive of RCS, however, the majority of published cases have mutations in PAX2, thus biasing the known information about the phenotype.     

Autosomal recessive otofaciocervical syndrome type 2 with novel homozygous small insertion in PAX1 gene

Otofaciocervical syndrome (OTFCS) is described as a single gene disorder of both autosomal dominant and autosomal recessive inheritance. The major clinical features of OTFCS include ear malformations (external/middle/inner ear), facial dysmorphism, shoulder girdle abnormalities, vertebral anomalies, and mild intellectual disability. The autosomal recessive form of OTFCS syndrome (OTFCS2) has been recently reported to be caused due to homozygous mutations in PAX1 gene. Here we report a third family of OTFCS2 phenotype wherein whole exome sequencing identified a novel homozygous small insertion in PAX1 as the underlying genetic cause.     

Paucity of skeletal manifestations in hispanic families with FBN1 mutations

Marfan syndrome (MFS) is an autosomal dominant condition with pleiotropic manifestations involving the skeletal, ocular, and cardiovascular systems. The diagnosis is based primarily on clinical involvement of these and other systems, referred to as the Ghent criteria. We have identified three Hispanic families from Mexico with cardiovascular and ocular manifestations due to novel FBN1 mutations but with paucity of skeletal features. The largest family, hMFS001, had a frameshift mutation in exon 24 (3075delC) identified as the cause of aortic disease in the family. Assessment of eight affected adults revealed no major skeletal manifestation of MFS. Family hMFS002 had a missense mutation (R1530C) in exon 37. Four members fulfilled the criteria for ocular and cardiovascular phenotype but lacked skeletal manifestations. Family hMFS003 had two consecutive missense FBN1 mutations (C515W and R516G) in exon 12. Eight members fulfilled the ocular criteria for MFS and two members had major cardiovascular manifestations, however none of them met criteria for skeletal system. These data suggest that individuals of Hispanic descent with FBN1 mutations may not manifest skeletal features of the MFS to the same extent as Caucasians. We recommend that echocardiogram, ocular examination and FBN1 molecular testing be considered for any patients with possible MFS even in the absence of skeletal features, including Hispanic patients.     

一个Waardenburg综合征Ⅱ型家系SOX10基因的突变分析CSCD

目的对1例Waardenburg综合征Ⅱ型先证者及其家系成员进行SOX10基因的突变分析,探讨其可能的分子生物学致病原因。方法抽提先证者及其家系成员的外周血基因组DNA,芯片捕获高通量测序方法对MITF、PAX3、SOX10、SNA12、END3和ENDRB基因的全部外显子及其侧翼序列进行检测。根据高通量测序结果,对先证者及其父母进行突变位点的Sanger测序验证分析。结果Sanger测序结果显示先证者存在SOX10C．127c〉T（P．R43X）杂合突变,导致SOX10基因第43位编码精氨酸的密码子（CGA）突变为终止密码子（UGA）,产生截短蛋白,影响蛋白质功能的正常发挥。经检索人类基因突变数据库,该突变为未报道过的新突变。患儿父母未检测到该突变。结论先证者SOX10基因C．127c〉T（P．R43X）杂合突变可能是其分子生物学致病原因。     

Interaction of the LMX1B and PAX2 gene products suggests possible molecular basis of differential phenotypes in Nail-Patella syndrome

The LMX1B gene, encoding a protein involved in limb, kidney and eye development, is mutated in patients affected by Nail-Patella syndrome. Inter- and intrafamilial variability is common in this disorder for skeletal abnormalities, presence and severity of nephropathy and ocular anomalies. Phenotypic variability might depend on interactions of the LMX1B causative gene with other genes during development of both kidney and eye, which might act as modifier genes. Results are presented on the interaction between LMX1B and PAX2 proteins, obtained by both direct yeast two-hybrid assay and coimmunoprecipitation. Such interaction provides support to further studies on pathways underlying important developmental processes.