Cilia are cellular organelles that are motile or non-motile and both types have important functions in the body ranging from moving extracellular fluids or propelling cells to transducing signals from the environment or from other cells. Ciliopathies are a group of human autosomal recessive conditions that result from abnormal ciliary function or structure and often present with multiple anomalies, often in midline organs. Many genes involved in genetic conditions such as Joubert syndrome or Oral-Facial-Digital syndrome are disrupted cilia genes that cause malformations with overlapping features including hydrocephalus and brain anomalies, microphthalmia, facial clefts, polydactyly, cystic kidneys and skeletal findings. TBC1D32 gene variants are associated with a severe ciliopathy with anomalies in the pituitary gland, eyes and brain. We report two cases of multiple anomalies on fetal ultrasound from two different families. The pregnancies were both interrupted via induction of delivery in the second trimester. Both fetal autopsies showed structural brain anomalies with extracranial midline findings including adrenal hypoplasia and genitourinary features secondary to absent pituitary gland. Although these features are similar to reported fetal cases in TBC1D32, TRIO-Whole Exome Sequencing identified pathogenic variants in a candidate gene, CDK20, a gene that plays a role in ciliogenesis in eukaryotic organisms. Congenital anomalies associated with CDK20 variants have not been reported prenatally, but in some individuals with developmental delay, seizures and behavioral disorders. Interestingly in mice and other model organisms, knock outs in gene homologs BROMI/TBC1D32 and CCRK/CDK20 cause ciliary defects similar to human ciliopathies. Together, we suggest that our fetal cases and such experimental observations support the hypothesis that TBC1D32 and CDK20 interact together and that as a result, pathogenic variants in both genes cause similar fetal phenotypes, thus expanding the spectrum of complex autosomal recessive human ciliopathies. More research is needed to functionally prove this important interaction as highlighted by the fetal autopsies and genetic testing in these cases.

CONTEXT:Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms.OBJECTIVE:This work aims to characterize the genetic associations and biochemical profile of mild IIH.METHODS:This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands.RESULTS:The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria.CONCLUSION:The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.

Objective Sonographic clues to the diagnosis of congenital myotonic dystrophy (CDM) are limited, particularly in the absence of family history of myotonic dystrophy (DM). We reviewed cases of CDM for unique prenatal findings. Study Design A single-center case series of fetuses with CMD with characteristic prenatal findings confirmed postnatally. Results Four fetuses with pre- or postnatally diagnosed CDM presented with macrocephaly in utero. While head measurements were appropriate for gestational age until midgestation, third-trimester head circumference and biparietal diameter were both >2 standard deviation (SD) above the mean in all. Abdominal and femur measurements were otherwise appropriate for gestation. Postnatally, the occipitofrontal circumference was >2 SD above the mean in all, confirming the diagnosis of macrocephaly. Conclusion CDM should be included in the differential diagnosis of third-trimester macrocephaly, especially in the presence of additional sonographic clues and when maternal medical history and physical examination are suggestive of DM.

American Journal of Medical Genetics Part AVolume 176, Issue 9 p. 2041-2043 CORRESPONDENCE An Additional Individual with a De Novo Variant in Myelin Regulatory Factor (MYRF) with Cardiac and Urogenital Anomalies: Further Proof of Causality: Comments on the article by Pinz et al. (†) David Chitayat, David Chitayat orcid.org/0000-0003-1944-7294 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorPatrick Shannon, Patrick Shannon Department of Pathology and laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorTami Uster, Tami Uster The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorMarjan M. Nezarati, Marjan M. Nezarati Genetics Program, North York General Hospital, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorRhonda E. Schnur, Rhonda E. Schnur GeneDx, Gaithersburg, MarylandSearch for more papers by this authorElizabeth J. Bhoj, Corresponding Author Elizabeth J. Bhoj bhoje@email.chop.edu orcid.org/0000-0001-5748-3507 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Correspondence Email: bhoje@email.chop.eduSearch for more papers by this author David Chitayat, David Chitayat orcid.org/0000-0003-1944-7294 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorPatrick Shannon, Patrick Shannon Department of Pathology and laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorTami Uster, Tami Uster The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorMarjan M. Nezarati, Marjan M. Nezarati Genetics Program, North York General Hospital, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorRhonda E. Schnur, Rhonda E. Schnur GeneDx, Gaithersburg, MarylandSearch for more papers by this authorElizabeth J. Bhoj, Corresponding Author Elizabeth J. Bhoj bhoje@email.chop.edu orcid.org/0000-0001-5748-3507 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Correspondence Email: bhoje@email.chop.eduSearch for more papers by this author First published: 02 August 2018 https://doi.org/10.1002/ajmg.a.40360Citations: 11Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume176, Issue9September 2018Pages 2041-2043 RelatedInformation

PURPOSE:KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the clinical spectrum of EOEE associated with KCNQ2 mutation.METHODS:A total of 239 patients with EOEE, including 51 cases with Ohtahara syndrome and 104 cases with West syndrome, were analyzed by high-resolution melting (HRM) analysis or whole-exome sequencing. Detailed clinical information including electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were collected from patients with KCNQ2 mutation.KEY FINDINGS:A total of nine de novo and one inherited mutations were identified (two mutations occurred recurrently). The initial seizures, which were mainly tonic seizures, occurred in the early neonatal period in all 12 patients. A suppression-burst pattern on EEG was found in most. Only three patients showed hypsarrhythmia on EEG; eight patients became seizure free when treated with carbamazepine, zonisamide, phenytoin, topiramate, or valproic acid. Although the seizures were relatively well controlled, moderate-to-profound intellectual disability was found in all except one patient who died at 3 months.SIGNIFICANCE:De novo KCNQ2 mutations are involved in EOEE, most of which cases were diagnosed as Ohtahara syndrome. These cases showed distinct features with early neonatal onset, tonic seizures, a suppression-burst EEG pattern, infrequent evolution to West syndrome, and good response to sodium channel blockers, but poor developmental prognosis. Genetic testing for KCNQ2 should be considered for patients with EOEE.

The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.

Although biallelic mutations in non-collagen genes account for 10 of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cistrans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.

Objective To report the prenatal findings and postnatal outcome of fetal ventriculomegaly associated with isolated large choroid plexus cysts (CPCs).Method Cases of isolated fetal ventriculomegaly and large CPCs (> 10 mm) were identified through a search of patient records from 2003 to 2006. Ultrasound (US) findings were reviewed: unilateral or bilateral ventriculomegaly, ventricular size, size of CPCs, and changes on serial scans. Correlation was made with fetal magnetic resonance imaging (MRI), pregnancy outcome, and long-term follow-up.Results Six cases of isolated large CPCs (12-30 mm) with ventriculomegaly (11-17 mm) were detected on US at 18 to 26 weeks of gestation. Serial prenatal US showed the CPCs resolved (one case) or decreased in size (five cases). Ventricular size became normal during pregnancy in five cases and decreased in size in one case. Fetal MRI performed in three cases showed no additional findings. Five patients had amniocentesis which showed normal karyotype. There was one termination of pregnancy (the fetus showed no abnormality on external examination). There were five healthy newborns, with follow-up to 4.5 years of age (one), 5.5 years (one), and 6 years (three). All had normal physical and developmental outcome.Conclusion Large isolated CPCs may transiently dilate the fetal cerebral ventricles. Follow-up to 6 years has shown normal growth and development. Copyright (C) 2011 John Wiley & Sons, Ltd.