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A human laterality disorder associated with a homozygous WDR16 deletion.

Ta-Shma A, Perles Z, Yaacov B, Werner M, Frumkin A, Rein AJ, Elpeleg O - Eur. J. Hum. Genet. (2014)

Bottom Line: The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown.The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning.Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.

ABSTRACT
The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.

No MeSH data available.


Related in: MedlinePlus

Abnormal arrangement of patients' organs (a) Echocardiogram of patient II-3 from the subcostal short axis view: A large azygos vein draining into the superior vena cava due to inferior vena cava interruption. (b) Schematic drawing of patient II-3 anatomy showing normal cardiac situs and inverted visceral arrangement: inferior vena cava interruption, azygos continuity to the superior vena cava, left-sided liver and right-sided stomach and spleen. (c) Chest X-ray of patient II-4 demonstrating SIT: the cardiac apex and the stomach bubble are to the right. (d) Schematic drawing of patient II-4 anatomy showing mirror image cardiac and visceral arrangement: dextrocardia, left-sided liver and right-sided stomach and spleen. Abbreviations: SVC, superior vena cava; IVC, inferior vena cava; RA, right atrium; Azyg, azygos vein.
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fig2: Abnormal arrangement of patients' organs (a) Echocardiogram of patient II-3 from the subcostal short axis view: A large azygos vein draining into the superior vena cava due to inferior vena cava interruption. (b) Schematic drawing of patient II-3 anatomy showing normal cardiac situs and inverted visceral arrangement: inferior vena cava interruption, azygos continuity to the superior vena cava, left-sided liver and right-sided stomach and spleen. (c) Chest X-ray of patient II-4 demonstrating SIT: the cardiac apex and the stomach bubble are to the right. (d) Schematic drawing of patient II-4 anatomy showing mirror image cardiac and visceral arrangement: dextrocardia, left-sided liver and right-sided stomach and spleen. Abbreviations: SVC, superior vena cava; IVC, inferior vena cava; RA, right atrium; Azyg, azygos vein.

Mentions: Patient II-3 is a female, the third child of consanguineous Palestinian parents (Figure 1a). Her birth and early development were uneventful. At 19 months of age, she was admitted because of acute gastroenteritis. The physical examination and chest X-ray demonstrated a left-sided heart and an US showed abdominal situs inversus. Echocardiogram demonstrated levocardia with interrupted inferior vena cava, all of which were consistent with HS (Figure 2a and b). Brain CT scan was normal, excluding hydrocephalus and her growth and development, followed till 7 years, were normal. Her younger brother, patient II-4, was brought to medical attention at 7 weeks of age because of viral bronchiolitis. Physical examination, chest X-ray and abdominal US were all consistent with SIT (Figure 2c and d). Nasal NO was normal (580 ppb) indicating normal ciliary function; electron microscopy examination of the nasal epithelium obtained by brush biopsy revealed normal ciliary structure, excluding PCD. On follow-up (current age 4 years), his growth and development were normal. The parents and two older sibs were healthy, with normal cardiac and abdominal situs determined by chest X-ray and abdominal US.


A human laterality disorder associated with a homozygous WDR16 deletion.

Ta-Shma A, Perles Z, Yaacov B, Werner M, Frumkin A, Rein AJ, Elpeleg O - Eur. J. Hum. Genet. (2014)

Abnormal arrangement of patients' organs (a) Echocardiogram of patient II-3 from the subcostal short axis view: A large azygos vein draining into the superior vena cava due to inferior vena cava interruption. (b) Schematic drawing of patient II-3 anatomy showing normal cardiac situs and inverted visceral arrangement: inferior vena cava interruption, azygos continuity to the superior vena cava, left-sided liver and right-sided stomach and spleen. (c) Chest X-ray of patient II-4 demonstrating SIT: the cardiac apex and the stomach bubble are to the right. (d) Schematic drawing of patient II-4 anatomy showing mirror image cardiac and visceral arrangement: dextrocardia, left-sided liver and right-sided stomach and spleen. Abbreviations: SVC, superior vena cava; IVC, inferior vena cava; RA, right atrium; Azyg, azygos vein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538206&req=5

fig2: Abnormal arrangement of patients' organs (a) Echocardiogram of patient II-3 from the subcostal short axis view: A large azygos vein draining into the superior vena cava due to inferior vena cava interruption. (b) Schematic drawing of patient II-3 anatomy showing normal cardiac situs and inverted visceral arrangement: inferior vena cava interruption, azygos continuity to the superior vena cava, left-sided liver and right-sided stomach and spleen. (c) Chest X-ray of patient II-4 demonstrating SIT: the cardiac apex and the stomach bubble are to the right. (d) Schematic drawing of patient II-4 anatomy showing mirror image cardiac and visceral arrangement: dextrocardia, left-sided liver and right-sided stomach and spleen. Abbreviations: SVC, superior vena cava; IVC, inferior vena cava; RA, right atrium; Azyg, azygos vein.
Mentions: Patient II-3 is a female, the third child of consanguineous Palestinian parents (Figure 1a). Her birth and early development were uneventful. At 19 months of age, she was admitted because of acute gastroenteritis. The physical examination and chest X-ray demonstrated a left-sided heart and an US showed abdominal situs inversus. Echocardiogram demonstrated levocardia with interrupted inferior vena cava, all of which were consistent with HS (Figure 2a and b). Brain CT scan was normal, excluding hydrocephalus and her growth and development, followed till 7 years, were normal. Her younger brother, patient II-4, was brought to medical attention at 7 weeks of age because of viral bronchiolitis. Physical examination, chest X-ray and abdominal US were all consistent with SIT (Figure 2c and d). Nasal NO was normal (580 ppb) indicating normal ciliary function; electron microscopy examination of the nasal epithelium obtained by brush biopsy revealed normal ciliary structure, excluding PCD. On follow-up (current age 4 years), his growth and development were normal. The parents and two older sibs were healthy, with normal cardiac and abdominal situs determined by chest X-ray and abdominal US.

Bottom Line: The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown.The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning.Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.

ABSTRACT
The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.

No MeSH data available.


Related in: MedlinePlus