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Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)?

Kruszka P, Uwineza A, Mutesa L, Martinez AF, Abe Y, Zackai EH, Ganetzky R, Chung B, Stevenson RE, Adelstein RS, Ma X, Mullikin JC, Hong SK, Muenke M - Mol Genet Genomic Med (2015)

Bottom Line: Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC.Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish.This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, Maryland.

ABSTRACT
Limb body wall complex (LBWC) and amniotic band sequence (ABS) are multiple congenital anomaly conditions with craniofacial, limb, and ventral wall defects. LBWC and ABS are considered separate entities by some, and a continuum of severity of the same condition by others. The etiology of LBWC/ABS remains unknown and multiple hypotheses have been proposed. One individual with features of LBWC and his unaffected parents were whole exome sequenced and Sanger sequenced as confirmation of the mutation. Functional studies were conducted using morpholino knockdown studies followed by human mRNA rescue experiments. Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC. Morpholino knockdown of iqck mRNA in the zebrafish showed ventral defects including failure of ventral fin to develop and cardiac edema. Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish. This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

No MeSH data available.


Related in: MedlinePlus

(A) Facial characteristics significant for hypertelorism, right cleft lip, short columella; (B) side profile showing scalp skin pedicle, depressed nasal bridge, malformed ear lobe and short columella; (C) scalp skin pedicle.
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fig02: (A) Facial characteristics significant for hypertelorism, right cleft lip, short columella; (B) side profile showing scalp skin pedicle, depressed nasal bridge, malformed ear lobe and short columella; (C) scalp skin pedicle.

Mentions: Another interesting consideration is a human homologue to the mouse disorganization (Ds) mutation (Robin and Nadeau 2001). A number of reports in the literature with skin pedicles and ABS findings propose a disorganization hypothesis. Skin pedicles are a rare finding, and previous described cases with skin pedicles resemble the two patients presented with LBWC in this report (Fig.2B and C) in a number of ways (Isidor et al. 2009; Temtamy et al. 2010). Isidor et al. presented four patients with skin pedicles and severe limb anomalies that were originally diagnosed as ABS, and proposed that these individuals resemble the disorganization phenotype in the mouse. Donnai and Winter first suggested that patients with ABS resembled the mouse with the yet to be found disorganization (Ds) mutation, and more reports as with features of ABS have suggested a human homologue to Ds, including patients with skin pedicles and limb anomalies (Donnai and Winter 1989; Lowry and Yong 1991; Nakamura and Nanjyo 1992; Robin et al. 2005). In one case, a ventral wall defect was reported (Donnai and Winter 1989). The Ds phenotype described by Hummel consisted of mice with a heterozygous mutation, homozygous lethal, that had many similarities to the ABS phenotype and to our two cases including neural tube defects, hamartomas represented by papillomas protruding from the body, limb anomalies, ventral wall defects, and facial clefting (Hummel 1959). The skin pedicle (Fig.2B and C) in our case was not biopsied; however, ten Donkelaar et al. (2002) did biopsy a similar scalp lesion in a boy who also had amputation-like hand defects and the biopsy showed evidence of a rudimentary meningocele. The multiple congenital anomalies presented in addition to the skin pedicle makes the phenotype presented in this study unique and possibly a new syndrome.


Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)?

Kruszka P, Uwineza A, Mutesa L, Martinez AF, Abe Y, Zackai EH, Ganetzky R, Chung B, Stevenson RE, Adelstein RS, Ma X, Mullikin JC, Hong SK, Muenke M - Mol Genet Genomic Med (2015)

(A) Facial characteristics significant for hypertelorism, right cleft lip, short columella; (B) side profile showing scalp skin pedicle, depressed nasal bridge, malformed ear lobe and short columella; (C) scalp skin pedicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585450&req=5

fig02: (A) Facial characteristics significant for hypertelorism, right cleft lip, short columella; (B) side profile showing scalp skin pedicle, depressed nasal bridge, malformed ear lobe and short columella; (C) scalp skin pedicle.
Mentions: Another interesting consideration is a human homologue to the mouse disorganization (Ds) mutation (Robin and Nadeau 2001). A number of reports in the literature with skin pedicles and ABS findings propose a disorganization hypothesis. Skin pedicles are a rare finding, and previous described cases with skin pedicles resemble the two patients presented with LBWC in this report (Fig.2B and C) in a number of ways (Isidor et al. 2009; Temtamy et al. 2010). Isidor et al. presented four patients with skin pedicles and severe limb anomalies that were originally diagnosed as ABS, and proposed that these individuals resemble the disorganization phenotype in the mouse. Donnai and Winter first suggested that patients with ABS resembled the mouse with the yet to be found disorganization (Ds) mutation, and more reports as with features of ABS have suggested a human homologue to Ds, including patients with skin pedicles and limb anomalies (Donnai and Winter 1989; Lowry and Yong 1991; Nakamura and Nanjyo 1992; Robin et al. 2005). In one case, a ventral wall defect was reported (Donnai and Winter 1989). The Ds phenotype described by Hummel consisted of mice with a heterozygous mutation, homozygous lethal, that had many similarities to the ABS phenotype and to our two cases including neural tube defects, hamartomas represented by papillomas protruding from the body, limb anomalies, ventral wall defects, and facial clefting (Hummel 1959). The skin pedicle (Fig.2B and C) in our case was not biopsied; however, ten Donkelaar et al. (2002) did biopsy a similar scalp lesion in a boy who also had amputation-like hand defects and the biopsy showed evidence of a rudimentary meningocele. The multiple congenital anomalies presented in addition to the skin pedicle makes the phenotype presented in this study unique and possibly a new syndrome.

Bottom Line: Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC.Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish.This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, Maryland.

ABSTRACT
Limb body wall complex (LBWC) and amniotic band sequence (ABS) are multiple congenital anomaly conditions with craniofacial, limb, and ventral wall defects. LBWC and ABS are considered separate entities by some, and a continuum of severity of the same condition by others. The etiology of LBWC/ABS remains unknown and multiple hypotheses have been proposed. One individual with features of LBWC and his unaffected parents were whole exome sequenced and Sanger sequenced as confirmation of the mutation. Functional studies were conducted using morpholino knockdown studies followed by human mRNA rescue experiments. Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC. Morpholino knockdown of iqck mRNA in the zebrafish showed ventral defects including failure of ventral fin to develop and cardiac edema. Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish. This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

No MeSH data available.


Related in: MedlinePlus