Locus and allelic heterogeneity and phenotypic variability in Waardenburg syndrome

Waardenburg syndrome (WS) is a disorder of neural crest cell migration characterized by auditory and pigmentary abnormalities. We investigated a cohort of 14 families (16 subjects) either by targeted sequencing or whole-exome sequencing. Thirteen of these families were clinically diagnosed with WS and one family with isolated non-syndromic hearing loss (NSHL). Intra-familial phenotypic variability and non-penetrance were observed in families diagnosed with WS1, WS2 and WS4 with pathogenic variants in PAX3, MITF and EDNRB, respectively. We observed gonosomal mosaicism for a variant in PAX3 in an asymptomatic father of two affected siblings. For the first time, we report a biallelic pathogenic variant in MITF in a subject with WS2 and a biallelic variant in EDNRB was noted in a subject with WS2. An individual with isolated NSHL carried a pathogenic variant in MITF. Blended phenotype of NSHL and albinism was observed in a subject clinically diagnosed to have WS2. A phenocopy of WS1 was observed in a subject with a reported pathogenic variant in GJB2, known to cause isolated NSHL. These novel and infrequently reported observations exemplify the allelic and genetic heterogeneity and show phenotypic diversity of WS.     

The association of Waardenburg syndrome and Hirschsprung megacolon

We describe four patients with Waardenburg syndrome and Hirschsprung aganglionic megacolon. In view of pathophysiologic relationships and animal studies, we conclude that the association of these two uncommon disorders is pathophysiologically significant.     

Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability

A screening program to detect Waardenburg syndrome (WS) conducted between 2002 and 2005, among 1,763 deaf individuals throughout Columbia identified 95 affected individuals belonging to 95 families, giving a frequency of 5.38% of WS among the institutionalized deaf population. We confirmed the clinical diagnosis of WS in the 95 propositi and, through the family evaluation, we also identified 45 non-institutionalized affected relatives. Audiologic, ophthalmologic, and genetic studies were performed to confirm the diagnosis. Following the classification of the WS consortium, based on the Waardenburg Index (WI), to define the type of WS. We classified 62.1% of the propositi as WS2 and 37.9% as WS1. We present here the results of the study of clinical manifestations, analyzing the presence, severity, and symmetry of clinical findings among this affected population. Overall, among the 95 propositi, in addition to sensorineural deafness in all, the most frequent features were broad nasal root (58.9%), a first degree relative affected (37.9%), heterochromia irides (36.8%), skin hypopigmentation (31.6%), white forelock (28.0%), intense blue iris (27.4%), synophrys (12.6%), premature graying (10.5%), ptosis of the eyelids (9.5%), and hypoplasia alae nasi (1.1%). The majority of individuals had normal psychomotor development (87%), while the remaining 13% had developmental delay. Among the latter, 9.4% corresponded to WS2 and 3.6% to WS1. Our data confirm an interesting inter- and intrafamilial variability in the phenotypic manifestations as well as extremely variable expression.     

Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome

The diagnosis of Marfan syndrome may be hampered by the existence of very mild and atypical cases as well as by marked intrafamilial variability. In these instances, molecular analysis of the fibrillin-1 gene (FBN1) can be helpful to identify individuals at risk. The underlying molecular mechanism for the clinical variability is presently unknown. We performed clinical and molecular studies in 36 subjects from three unrelated families. Expression studies of both FBN1 alleles were performed and related to the clinical severity. In family 1, an overlapping phenotype between Marfan syndrome (MFS) and Weill-Marchesani syndrome is presented. The diagnosis necessitated molecular studies and clinical examination in first-degree relatives. In family 2, the young proband presented with a phenotype overlapping between MFS and the kyphoscoliotic type of Ehlers-Danlos syndrome. Follow-up over time and identification of a FBN1 mutation allowed confirmation of the diagnosis. Mutation analysis enabled us to identify family members with mild expression. Family 3 illustrates the extensive intrafamilial variability in the clinical severity of MFS. Identification of a FBN1 mutation was helpful to identify subjects with mild expression and for the timely diagnosis in a neonate. In families 2 and 3, the relative expression of both FBN1 alleles was not related to clinical severity. We demonstrated that confirmation of the diagnosis of MFS may require detailed and repeated clinical evaluation and thorough family history taking. FBN1 mutation analysis is supportive for the diagnosis in mild and atypical presentations.     

Waardenburg syndrome: Novel mutations in a large Brazilian sample

This paper deals with the molecular investigation of Waardenburg syndrome (WS) in a sample of 49 clinically diagnosed probands (most from southeastern Brazil), 24 of them having the type 1 (WS1) variant (10 familial and 14 isolated cases) and 25 being affected by the type 2 (WS2) variant (five familial and 20 isolated cases). Sequential Sanger sequencing of all coding exons of PAX3, MITF, EDN3, EDNRB, SOX10 and SNAI2 genes, followed by CNV detection by MLPA of PAX3, MITF and SOX10 genes in selected cases revealed many novel pathogenic variants. Molecular screening, performed in all patients, revealed 19 causative variants (19/49?=?38.8%), six of them being large whole-exon deletions detected by MLPA, seven (four missense and three nonsense substitutions) resulting from single nucleotide substitutions (SNV), and six representing small indels. A pair of dizygotic affected female twins presented the c.430delC variant in SOX10, but the mutation, imputed to gonadal mosaicism, was not found in their unaffected parents. At least 10 novel causative mutations, described in this paper, were found in this Brazilian sample. Copy-number-variation detected by MLPA identified the causative mutation in 12.2% of our cases, corresponding to 31.6% of all causative mutations. In the majority of cases, the deletions were sporadic, since they were not present in the parents of isolated cases. Our results, as a whole, reinforce the fact that the screening of copy-number-variants by MLPA is a powerful tool to identify the molecular cause in WS patients.     

Phenotypic variability in Meckel–Gruber syndrome

Five Bedouin sibs are described with Meckel-Gruber syndrome (MGS), an autosomal recessive disorder with multiple abnormalities. Each affected sib manifested only two of the three cardinal signs of MGS: occipital encephalocele and polycystic kidneys, lacking polydactyly. The phenotypic variability of the MGS pleiotropic gene is briefly discussed.     

Clinical variability of genetic isolates of Cohen syndrome

Cohen syndrome (CS) (OMIM#216550) is an uncommon autosomal recessive developmental disorder that has been attributed to mutations in the COH1 gene in at least 200 patients of diverse ethnic background so far. The clinical heterogeneity of CS is evident when comparing patients of different ethnic backgrounds, especially when evaluating specific system phenotypes separately, such as the ophthalmic and central nervous systems. We reviewed the available clinical data on CS cohorts of patients who share a founder effect and demonstrated that most features associated so far with CS are less than those always present in the patients who share a founder mutation thus representing clinical heterogeneity. Furthermore, there is a wide clinical variability of CS in the distinct founder mutation cohorts, the Finnish, Greek/Mediterranean, Amish and Irish travelers. The Greek/Mediterranean founder mutation is correlated to a CS phenotype characterized by specific and persistent skeletal features, corneal changes, periodontal disease, a distinct neurocognitive phenotype for the high recurrence of autism and non-verbal communication and inconstant microcephaly.     

Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C)

A study of 73 patients with the Sanfilippo syndrome (36 patients with Sanfilippo A disease, 23 with Sanfilippo B disease and 14 with Sanfilippo C disease) revealed both intertype and intratype variability. The course of the disease was relatively mild in Sanfilippo B disease and dementia was less severe. Type A showed earlier onset with more severe clinical manifestations and an earlier age at death. Sanfilippo C disease was slightly less severe than Sanfilippo A disease. The intratype variability may be explained in part by differences in genetic and environmental background. In Sanfilippo B disease, genetic heterogeneity is suggested by the observation of a more severe and a mild variant, and this variation may be due to the involvement of different allelic mutations. The intra-familial variability of the different types was small, but in three families with Sanfilippo B disease intrafamilial variability was evident.     

Germ-line mosaicism in Waardenburg syndrome

A family with three children with Waardenburg syndrome born to normal, unrelated parents is reported. This appears to be the first report suggesting germ-line mosaicism in Waardenburg syndrome.     

The clinical manifestations of Degos' syndrome

Pathologic mechanisms underlying Degos' syndrome are poorly characterized. Thrombosis, either as a consequence of a postulated vasculitis or as a primary defect, is often a clinical complication of this syndrome. We have studied multiple coagulation parameters, including potential defects in fibrin assembly and other adhesive proteins, in a patient with Degos' syndrome and found no specific abnormality to explain the pathologic features of this syndrome. An extensive literature review as well as detailed biochemical and biophysical coagulation studies are presented. The alternative possibility of Degos' syndrome as a mucinosis is discussed.     

Phenotypic discriminants in the Waardenburg syndrome

The gene for Waardenburg syndrome (WS) has been assigned to the locus 2q37 and further molecular investigations of affected families are now urgently required to explore the question of possible genetic heterogeneity. Firm positive or negative diagnosis in family members is crucial for studies of this type, but great variation in phenotypic expression sometimes makes this a difficult matter. Ethnic variation in craniofacial anatomical relationships further complicates the issue. We have attempted to establish diagnostic criteria for WS on the basis of an analysis of the phenotypes in 68 affected children who have been examined in special schools for the deaf in Southern Africa during the past 18 years. We then used these criteria for diagnostic evaluation of all available persons in seven multigeneration WS families in the Cape, as a preliminary to molecular investigations. With very few exceptions this approach permitted firm positive or negative diagnosis in these individuals.     

Cx26 deafness: mutation analysis and clinical variability

Mutations in the gap junction protein connexin 26 (Cx26) gene (GJB2) seem to account for many cases of congenital sensorineural hearing impairment, the reported prevalence being 34-50% in autosomal recessive cases and 10-37% in sporadic cases. The hearing impairment in these patients has been described as severe or profound. We have studied 53 unrelated subjects with congenital non-syndromic sensorineural hearing impairment in order to evaluate the prevalence and type of Cx26 mutations and establish better genotype-phenotype correlation. Mutations in the Cx26 gene were found in 53% of the subjects tested, 35.3% of the autosomal recessive and 60% of the sporadic cases in our series. Three new mutations were identified. The hearing deficit varied from mild to profound even in 35delG homozygotes within the same family. No evidence of progression of the impairment was found.Alterations of the Cx26 gene account for a large proportion of cases of congenital non-syndromic sensorineural deafness, so it seems appropriate to extend the molecular analysis even to subjects with mild or moderate prelingual hearing impairment of unknown cause.