J Pediatr Genet 2023; 12(03): 246-253
DOI: 10.1055/s-0041-1733940
Case Based Review

Novel Pathogenic DNAH5 Variants in Primary Ciliary Dyskinesia: Association with Visceral Heterotaxia and Neonatal Cholestasis

Hong T. Lin
1   College of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
,
Anita Gupta
2   Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Kevin E. Bove
2   Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Sara Szabo
2   Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Fang Xu
3   PreventionGenetics, Marshfield, Wisconsin, United States
,
Anthony Krentz
3   PreventionGenetics, Marshfield, Wisconsin, United States
,
Amelle L. Shillington
4   Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
› Author Affiliations

Abstract

The dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the DNAH5 locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis. Genetic testing indicated that the patient is a compound heterozygote with a pathogenic c.8498G > A (known as pathogenic) on the maternally derived allele and two variants of uncertain significance, c.1206T > A and c.7800T > G, on the paternally derived allele. As PCD is autosomal recessive, we conclude that one, or both, of these paternally derived variants are pathogenic. To our knowledge, this is the first time that the clinical implications of c.1206T > A (p.Asn402Lys) and c.7800T > G (p.Ile2600Met) are documented. Furthermore, we use this case as an example to recommend clinicians to assess for PCD and laterality defects when presented with severe infantile cholestasis. While the association of cholestasis with PCD is relatively uncommon, PCD is a risk factor for increased prevalence of biliary atresia and infections, both of which are known causes of cholestasis in early infancy.



Publication History

Received: 28 November 2020

Accepted: 23 February 2021

Article published online:
17 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Mirra V, Werner C, Santamaria F. Primary ciliary dyskinesia: an update on clinical aspects, genetics, diagnosis, and future treatment strategies. Front Pediatr 2017; 5: 135
  • 2 Zariwala MA, Knowles MR, Omran H. Genetic defects in ciliary structure and function. Annu Rev Physiol 2007; 69 (01) 423-450
  • 3 Ferkol TW, Leigh MW. Ciliopathies: the central role of cilia in a spectrum of pediatric disorders. J Pediatr 2012; 160 (03) 366-371
  • 4 Oda T, Abe T, Yanagisawa H, Kikkawa M. Structure and function of outer dynein arm intermediate and light chain complex. Mol Biol Cell 2016; 27 (07) 1051-1059
  • 5 Hornef N, Olbrich H, Horvath J. et al. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med 2006; 174 (02) 120-126
  • 6 Vaisberg EA, Koonce MP, McIntosh JR. Cytoplasmic dynein plays a role in mammalian mitotic spindle formation. J Cell Biol 1993; 123 (04) 849-858
  • 7 Dodding MP, Way M. Coupling viruses to dynein and kinesin-1. EMBO J 2011; 30 (17) 3527-3539
  • 8 Tarkar A. The role of DYX1C1 in motile cilia and axonemal dynein assembly. UCONN Lib. Accessed 2015 at: https://archives.lib.uconn.edu/islandora/object/20002%3A860648964
  • 9 Yang P, Diener DR, Yang C. et al. Radial spoke proteins of Chlamydomonas flagella. J Cell Sci 2006; 119 (Pt 6): 1165-1174
  • 10 Shah AS, Ben-Shahar Y, Moninger TO, Kline JN, Welsh MJ. Motile cilia of human airway epithelia are chemosensory. Science 2009; 325 (5944): 1131-1134
  • 11 Jain R, Javidan-Nejad C, Alexander-Brett J. et al. Sensory functions of motile cilia and implication for bronchiectasis. Front Biosci (Schol Ed) 2012; 4: 1088-1098
  • 12 Michaud EJ, Yoder BK. The primary cilium in cell signaling and cancer. Cancer Res 2006; 66 (13) 6463-6467
  • 13 Larusso NF, Masyuk TV. The role of cilia in the regulation of bile flow. Dig Dis 2011; 29 (01) 6-12
  • 14 Raman R, Al-Ali SY, Poole CA, Dawson BV, Carman JB, Calder L. Isomerism of the right atrial appendages: clinical, anatomical, and microscopic study of a long-surviving case with asplenia and ciliary abnormalities. Clin Anat 2003; 16 (03) 269-276
  • 15 Ware SM, Aygun MG, Hildebrandt F. Spectrum of clinical diseases caused by disorders of primary cilia. Proc Am Thorac Soc 2011; 8 (05) 444-450
  • 16 Greenstone MA, Jones RW, Dewar A, Neville BG, Cole PJ. Hydrocephalus and primary ciliary dyskinesia. Arch Dis Child 1984; 59 (05) 481-482
  • 17 Wallmeier J, Nielsen KG, Kuehni CE. et al. Motile ciliopathies. Nat Rev Dis Primers 2020; 6 (01) 77
  • 18 Delemos AS, Friedman LS. Systemic causes of cholestasis. Clin Liver Dis 2013; 17 (02) 301-317
  • 19 Bush A, Chodhari R, Collins N. et al. Primary ciliary dyskinesia: current state of the art. Arch Dis Child 2007; 92 (12) 1136-1140
  • 20 Rumman N, Jackson C, Collins S, Goggin P, Coles J, Lucas JS. Diagnosis of primary ciliary dyskinesia: potential options for resource-limited countries. Eur Respir Rev 2017; 26 (143) 160058
  • 21 Behan L, Dimitrov BD, Kuehni CE. et al. PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia. Eur Respir J 2016; 47 (04) 1103-1112
  • 22 Damseh N, Quercia N, Rumman N, Dell SD, Kim RH. Primary ciliary dyskinesia: mechanisms and management. Appl Clin Genet 2017; 10: 67-74
  • 23 Shapiro AJ, Zariwala MA, Ferkol T. et al; Genetic Disorders of Mucociliary Clearance Consortium. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatr Pulmonol 2016; 51 (02) 115-132
  • 24 Kobbernagel H, Buchvald FF, Haarman EG. et al. Late breaking abstract - efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia: the BESTCILIA randomized placebo-controlled trial. Eur Respir J 2019;54(Suppl 63). DOI: 10.1183/13993003.congress-2019.RCT5102
  • 25 Valery PC, Morris PS, Byrnes CA. et al. Long-term azithromycin for Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study): a multicentre, double-blind, randomised controlled trial. Lancet Respir Med 2013; 1 (08) 610-620
  • 26 Kuehni CE, Frischer T, Strippoli M-PF. et al; ERS Task Force on Primary Ciliary Dyskinesia in Children. Factors influencing age at diagnosis of primary ciliary dyskinesia in European children. Eur Respir J 2010; 36 (06) 1248-1258
  • 27 Coren ME, Meeks M, Morrison I, Buchdahl RM, Bush A. Primary ciliary dyskinesia: age at diagnosis and symptom history. Acta Paediatr 2002; 91 (06) 667-669
  • 28 Shoemark A, Boon M, Brochhausen C. et al; representing the BEAT-PCD Network Guideline Development Group. International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria). Eur Respir J 2020; 55 (04) 1900725
  • 29 Chu AS, Russo PA, Wells RG. Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Mod Pathol 2012; 25 (05) 751-757
  • 30 Xia X, Francis H, Glaser S, Alpini G, LeSage G. Bile acid interactions with cholangiocytes. World J Gastroenterol 2006; 12 (22) 3553-3563
  • 31 Ma N, Zhang JZ, Itzhaki I. et al. Determining the pathogenicity of a genomic variant of uncertain significance using cRISPR/Cas9 and human-induced pluripotent stem cells. Circulation 2018; 138 (23) 2666-2681