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Joubert syndrome (JS), a well-established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. Exome sequencing detected a de novo heterozygous missense variant in SLC30A7: NM_133496.5: c.407 T > C, (p.Val136Ala). The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. A de novo deletion-insertion variant in SLC30A7, c.490_491delinsAG (p.His164Ser) was found. Both de novo variants affect highly conserved residues. Variants were not identified in known Joubert genes for either case. SLC30A7 has not yet been associated with a human phenotype. The SLC30 family of zinc transporters, like SLC30A7, permit cellular efflux of zinc, and although it is expressed in the brain its functions remain unknown. Published data from proteomic studies support SLC30A7 interaction with TCTN3, another protein associated with JS. The potential involvement of such genes in primary cilia suggest a role in Sonic Hedgehog signaling. SLC30A7 is a candidate JS-associated gene. Future work could be directed toward further characterization of SLC30A7 variants and understanding its function., (© 2022 Wiley Periodicals LLC.)

Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A underlying the etiology of RS. The aforementioned "Robinow-associated genes" and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene-targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1, ROR2, and NXN. One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN, which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS., (© 2020 Wiley Periodicals LLC.)

Biallelic loss-of-function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM #615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal-onset epilepsy with fever-sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu-mediated rearrangement; confirmed by break-point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read-depth-based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved., (© 2021 Wiley Periodicals LLC.)

Background: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population., Methods: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW., Results: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023)., Conclusions: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients., (© 2020 Wiley Periodicals, Inc.)

We studied two brothers who presented in the newborn period with cardiac, renal, and hepatic anomalies that were initially suggestive of ALGS, although no mutations in JAG1 or NOTCH2 were identified. Exome sequencing demonstrated compound heterozygous mutations in the NEK8 gene (Never in mitosis A-related Kinase 8), a ciliary kinase indispensable for cardiac and renal development based on murine studies. The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain. The RCC1 domain is crucial for localization of the NEK8 protein to the centrosomes and cilia. Mutations in NEK8 have been previously reported in three fetuses (from a single family) with renal-hepatic-pancreatic dysplasia 2 (RHPD2), similar to Ivemark syndrome, and in three individuals with nephronophthisis (NPHP9). This is the third report of disease-causing mutations in the NEK8 gene in humans and only the second describing multi-organ involvement. The clinical features we describe differ from those in the previously published report in that (1) a pancreatic phenotype was not observed in the individuals reported here, (2) there were more prominent cardiac findings, (consistent with observations in murine models), and (3) we observed bile duct hypoplasia rather than ductal plate malformation. The patients reported here expand our understanding of the NEK8-associated phenotype. Our findings highlight the variable phenotypic expressivity and the spectrum of clinical manifestations due to mutations in the NEK8 gene., (© 2015 Wiley Periodicals, Inc.)

Alagille syndrome is a multisystem developmental disorder characterized by bile duct paucity, congenital heart disease, vertebral anomalies, posterior embryotoxon, and characteristic facial features. Alagille syndrome is typically the result of germline mutations in JAG1 or NOTCH2 and is one of several human diseases caused by Notch signaling abnormalities. A wide phenotypic spectrum has been well documented in Alagille syndrome. Therefore, monozygotic twins with Alagille syndrome provide a unique opportunity to evaluate potential phenotypic modifiers such as environmental factors or stochastic effects of gene expression. In this report, we describe an Alagille syndrome monozygotic twin pair with discordant placental and clinical findings. We propose that environmental factors such as prenatal hypoxia may have played a role in determining the phenotypic severity., (© 2015 Wiley Periodicals, Inc.)