Homozygous NEK8 Mutations in Siblings With Neonatal Cholestasis Progressing to End‐stage Liver, Renal, and Cardiac Disease

Abstract

N eonatal cholestasis (NC) affects 1 in 2500 term infants with varying etiologies (1). Ciliopathies constitute a group of genetic disorders associated with ciliary dysfunction leading to multiorgan involvement that can present with cholestasis (2). We report 2 siblings who presented with NC and paucity of bile ducts. They subsequently developed end-stage liver (ESLD) and renal disease (ESRD) with severe progressive cardiac dysfunction. A novel homozygous variant in the NEK8 (never in mitosis A-related kinase A) gene, associated with the multiorgan ciliopathy Nephronophthisis (NPHP) type 9, was identified in both siblings (3). INDEX PATIENTThe patient (IV-3, Supplement Fig. 1A, Supplemental Digital Content, http://links.lww.com/MPG/B726) was born male, fullterm, to healthy, consanguineous parents. He had worsening direct hyperbilirubinemia of 14 with elevated gamma-glutamyl transferase (GGT) up to 2306 units/L, within the first 2 weeks of life (Supplemental Table 1, Supplemental Digital Content, http:// links.lww.com/MPG/B726). Infectious workup was nonrevealing. Abdominal ultrasound showed normal liver echogenicity without hepatic masses or intrahepatic ductal dilatation and 2 small kidneys. An intraoperative cholangiogram excluded biliary atresia (BA). The liver biopsy demonstrated paucity of interlobular bile ducts, cholangiolar proliferation, cholestasis, and mild bridging fibrosis (Fig. 1A and B). Genetic testing for Alagille syndrome including JAG1 deletion/duplication, progressive familial intrahepatic cholestasis (PFIC) and bile acid synthesis disorders (BASD) was negative. An echocardiogram showed

Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients

“…ciliopathy related genes), lack of functional evidence, and no repletion in patients. 34,35 Although our findings need to be confirmed by functional analyses, and future patients with similar genotype and phenotype, available evidence maybe sufficient for better identification of pathogenic variants in NOTCH2 and minimizing missed diagnosis of ALGS type2.…”

“…Four previously reported variants (c.4699C > T/p.Arg1567Trp, c.4819C > T/p.Arg1607Cys, c.4967A > G/p.Gln1656Arg and c.5314G > A/p.Glu1772Ly) can be re‐defined as benign for the presence of allele frequencies in gnomAD, not excluding other genetic disorders with similar phenotype (i.e. ciliopathy related genes), lack of functional evidence, and no repletion in patients 34,35 …”

NEK8-Associated Nephropathies: Do Autosomal Dominant Forms Exist?

“…In humans, NEK8 has been linked to two autosomal recessive diseases: NPHP9 (MIM#613824) and renal-hepatic-pancreatic dysplasia 2 (MIM#615415). Reported mutations are scattered throughout the protein comprising its N-terminal kinase domain and five C-terminal regulator of chromosome condensation 1 (RCC1) repeat domains [13, 17]. Genotype-phenotype studies did not correlate between the mutated protein domain and the phenotype [13, 17].…”

“…Reported mutations are scattered throughout the protein comprising its N-terminal kinase domain and five C-terminal regulator of chromosome condensation 1 (RCC1) repeat domains [13, 17]. Genotype-phenotype studies did not correlate between the mutated protein domain and the phenotype [13, 17]. They rather showed that the severe forms of the disease characterized by enlarged cystic kidneys and pancreas associated with proliferative cystic biliary ducts are linked to total loss of function NEK8 variants [3, 13], while homozygous missense variants thought to lead to a gain of function of the NEK8 are linked to asymmetric dysplastic/hypodysplastic kidneys with loss of differentiation, cortical interstitial fibrosis, dilated tubules, and cartilage nodules, associated with paucity of bile ducts [13].…”

Renal–hepatic–pancreatic dysplasia-1 with a novel NPHP3 genotype: a case report and review of the literature

“…Mutational analysis of coding sequences did not reveal any pathogenic variant in NPHP3 ; nonetheless, the fetal phenotype and laser capture data support the model of a paternally transmitted autosomal recessive disorder that occurred because of ABM. Frank et al reported a case of RHPD2 caused by a NEK8 pathogenic variant; however, this case had a phenotype consistent with RHPD1 [ 24 , 25 ]. Pathogenic variants in NEK8 on chromosome 17q11 result in RHPD2.…”