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Phenotypic and genetic characterization of a family carrying two Xq21.1-21.3 interstitial deletions associated with syndromic hearing loss.

Iossa S, Costa V, Corvino V, Auletta G, Barruffo L, Cappellani S, Ceglia C, Cennamo G, D'Adamo AP, D'Amico A, Di Paolo N, Forte R, Gasparini P, Laria C, Lombardo B, Malesci R, Vitale A, Marciano E, Franzè A - Mol Cytogenet (2015)

Bottom Line: We identified two, previously unreported, Xq21.1-21.3 interstitial deletions.The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity.However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

View Article: PubMed Central - PubMed

Affiliation: DMMBM, Università di Napoli "Federico II", Naples, Italy ; Ceinge Biotecnologie Avanzate, Naples, Italy.

ABSTRACT

Background: Sensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability.

Results: Clinical analyses revealed a very complex phenotype that included inner ear malformations, vestibular problems, choroideremia and hypotonia with a peculiar pattern of phenotypic variability. Genomic analysis revealed, for the first time, the presence of two close interstitial deletions in the Xq21.1-21.3, harboring 11 protein coding, 9 non-coding genes and 19 pseudogenes. Among these, 3 protein coding genes have already been associated with X-linked hearing loss, intellectual disability and choroideremia.

Conclusions: In this study we highlighted the presence of peculiar genotypic and phenotypic details in a family affected by syndromic X-linked hearing loss with intellectual disability. We identified two, previously unreported, Xq21.1-21.3 interstitial deletions. The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity. However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

No MeSH data available.


Related in: MedlinePlus

Pedigree of the affected Italian family. Squares and circles symbolize males and females, respectively. Unblackened and blackened symbols denote unaffected and affected individuals, respectively. Circles with a dot inside denote carrier females. Diagonal lines denote deceased individuals. The arrow denotes the proband.
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Fig1: Pedigree of the affected Italian family. Squares and circles symbolize males and females, respectively. Unblackened and blackened symbols denote unaffected and affected individuals, respectively. Circles with a dot inside denote carrier females. Diagonal lines denote deceased individuals. The arrow denotes the proband.

Mentions: A four-generation Italian family (Figure 1) with an X-linked syndromic form of hearing impairment was studied. The proband (IV-1) and his brother (IV-2) had congenital bilateral hearing SNHL that had been assessed by our group a few months after birth as described in Chinetti et al. [21]. At 2 years of age both individuals showed psycho-neuro-motor disabilities too, with different degrees of severity. In the course of this study, several other clinical signs, summarized in Table 1, were observed. In detail: proband (IV-1) born in 2006, was diagnosed with bilateral severe hearing SNHL at 5 months of age. At 2 years of age, he was diagnosed with psycho-neuro-motor disability. He presented also trunk and limb hypotonicity, poor motor coordination, and was unable to walk unsupported. He was fitted with hearing aids by 6 months of age, but since January 2012 has refused to use them. At present, the ID is profound with no evolutive process. Comprehension is very poor; he recognizes only the use and function of simple and familiar objects. Verbal language is absent and he use a mimic sign language with motor stereotypies. He presents a psychotic behavioral and relational disorder. He presents balance problems and flat feet too. Proband’s brother (IV-2) born in 2007, was diagnosed at 5 months with a SNHL similar to the proband. Subsequently, at about 2 years of age, he was also diagnosed with trunk and limbs hypotonicity and psycho-neuro-motor disability. At present, he presents a phenotype similar to that of his brother but in a much milder form. Like his brother, he recognizes only the use and function of simple and familiar objects. Verbal language and comprehension, in spite of constant hearing aid use, is poor, but better than that of his elder brother.Figure 1


Phenotypic and genetic characterization of a family carrying two Xq21.1-21.3 interstitial deletions associated with syndromic hearing loss.

Iossa S, Costa V, Corvino V, Auletta G, Barruffo L, Cappellani S, Ceglia C, Cennamo G, D'Adamo AP, D'Amico A, Di Paolo N, Forte R, Gasparini P, Laria C, Lombardo B, Malesci R, Vitale A, Marciano E, Franzè A - Mol Cytogenet (2015)

Pedigree of the affected Italian family. Squares and circles symbolize males and females, respectively. Unblackened and blackened symbols denote unaffected and affected individuals, respectively. Circles with a dot inside denote carrier females. Diagonal lines denote deceased individuals. The arrow denotes the proband.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4376344&req=5

Fig1: Pedigree of the affected Italian family. Squares and circles symbolize males and females, respectively. Unblackened and blackened symbols denote unaffected and affected individuals, respectively. Circles with a dot inside denote carrier females. Diagonal lines denote deceased individuals. The arrow denotes the proband.
Mentions: A four-generation Italian family (Figure 1) with an X-linked syndromic form of hearing impairment was studied. The proband (IV-1) and his brother (IV-2) had congenital bilateral hearing SNHL that had been assessed by our group a few months after birth as described in Chinetti et al. [21]. At 2 years of age both individuals showed psycho-neuro-motor disabilities too, with different degrees of severity. In the course of this study, several other clinical signs, summarized in Table 1, were observed. In detail: proband (IV-1) born in 2006, was diagnosed with bilateral severe hearing SNHL at 5 months of age. At 2 years of age, he was diagnosed with psycho-neuro-motor disability. He presented also trunk and limb hypotonicity, poor motor coordination, and was unable to walk unsupported. He was fitted with hearing aids by 6 months of age, but since January 2012 has refused to use them. At present, the ID is profound with no evolutive process. Comprehension is very poor; he recognizes only the use and function of simple and familiar objects. Verbal language is absent and he use a mimic sign language with motor stereotypies. He presents a psychotic behavioral and relational disorder. He presents balance problems and flat feet too. Proband’s brother (IV-2) born in 2007, was diagnosed at 5 months with a SNHL similar to the proband. Subsequently, at about 2 years of age, he was also diagnosed with trunk and limbs hypotonicity and psycho-neuro-motor disability. At present, he presents a phenotype similar to that of his brother but in a much milder form. Like his brother, he recognizes only the use and function of simple and familiar objects. Verbal language and comprehension, in spite of constant hearing aid use, is poor, but better than that of his elder brother.Figure 1

Bottom Line: We identified two, previously unreported, Xq21.1-21.3 interstitial deletions.The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity.However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

View Article: PubMed Central - PubMed

Affiliation: DMMBM, Università di Napoli "Federico II", Naples, Italy ; Ceinge Biotecnologie Avanzate, Naples, Italy.

ABSTRACT

Background: Sensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability.

Results: Clinical analyses revealed a very complex phenotype that included inner ear malformations, vestibular problems, choroideremia and hypotonia with a peculiar pattern of phenotypic variability. Genomic analysis revealed, for the first time, the presence of two close interstitial deletions in the Xq21.1-21.3, harboring 11 protein coding, 9 non-coding genes and 19 pseudogenes. Among these, 3 protein coding genes have already been associated with X-linked hearing loss, intellectual disability and choroideremia.

Conclusions: In this study we highlighted the presence of peculiar genotypic and phenotypic details in a family affected by syndromic X-linked hearing loss with intellectual disability. We identified two, previously unreported, Xq21.1-21.3 interstitial deletions. The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity. However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

No MeSH data available.


Related in: MedlinePlus