The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

Hale, Andrew T.; Boudreau, Hunter; Devulapalli, Rishi; Duy, Phan Q.; Atchley, Travis J.; Dewan, Michael C.; Goolam, Mubeen; Fieggen, Graham; Spader, Heather L.; Smith, Anastasia A.; Blount, Jeffrey P.; Johnston, James M.; Rocque, Brandon G.; Rozzelle, Curtis J.; Chong, Zechen; Strahle, Jennifer M.; Schiff, Steven J.; Kahle, Kristopher T.

doi:10.1186/s12987-024-00513-z

Fluids and Barriers of the CNS

Table 5 Ciliopathy

From: The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

Citation	Title	Author affiliation	Case #	Ancestry	Study design	CNS phenotype	Non-CNS phenotype	Type of hydrocephalus	Genetic methodology	Genetic analysis	Inheritance	Genetic findings
Alby et al., 2015 [249]	Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome	Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, Paris, France	8 Subjects, Controls used	Romania, Hungary, Kosovo, Lebanon	Case study	Anencephaly or large occipital meningocele to vermian agenesis, associated with brainstem anomalies	Cleft lip and palate, polysyndactyly, preaxial polydactyly of the feet	-	TES	NGS; CNV	AR	14q23.1 (c.C230G, p.S77X in exon 2 and c.G1815A of exon 14 in KIAA0586)
Al-Shroof et al., 2001 [250]	Ciliary dyskinesia associated with hydrocephalus and mental retardation in a Jordanian family	Houston Medical Center, Warner Robins, GA, USA	4 Subjects, 5 Family Members	Jordanian	Case study	Intellectual disability	Growth delay	Communicating	Chromosome analysis	Haplotype analysis	AR	-
Bachmann-Gagescu et al., 2012 [251]	Genotype–phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures	University of Washington, Seattle, Washington, USA	20 Subjects, Controls used	-	Case series	Intellectual impairment, hypotonia, ataxia, molar tooth sign	Retinal dystrophy, chorioretinal coloboma, cystic kidney disease, liver fibrosis and polydactyly	Obstructive	TGS	Variant analysis; microsatellite marker assay; a-CGH, SNP	AR	4p15.32 (CC2D2A mutations: p.S117R; p.IVS11(+ 1); p.S423Gfs19; p.K507E; p.L559P; p.R950X; p.R1019X; p.R1049X; p.V1097Ffs1; p.V1045A; p.Q1096H; p.T1116M; p.P1122S; p.V1151A; p.IVS29(-1); p.V1298Ffs16; p.IVS30(-3); p.E1393Efs1; p.R1284C; p.R1284H; p.R1330Q; p.V1430A; p.R1528C; p.D1556V; p.S1615Lfs*15)
Bondeson et al., 2017 [252]	A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy	Uppsala University, Science for Life Laboratory, Uppsala, Sweden	5 Subjects, Controls used	Swedish	Case study	Liquified skull, cerebral cysts, encephalocele	Bilateral club foot, renal cysts, neck hygroma, single umbilical artery	-	WES	Sanger Sequencing; haplotype analysis	AR	10q23.33 (c.C256T, p.R86X in exon 3 of CEP55)
Boycott et al., 2007 [253]	Meckel syndrome in the Hutterite population is actually a Joubert-related cerebello-oculo-renal syndrome	Alberta Children's Hospital and University of Calgary, Calgary, Alberta, Canada	10 Subjects	Hutterite	Case series	Developmental delay, hypotonia, ataxia, abnormal breathing pattern, nystagmus, strabismus	Growth failure, retinal colobomas, post-axial polydactyly, cystic kidneys, abnormalities in renal function, hypertension, occipital encephalocele, posterior fossa fluid collections	Obstructive	TGS	Microsatellite marker assay	AR	Genetic analysis unrevealing
Dawe et al., 2007 [254]	The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation	University of Oxford, South Parks Road, Oxford OX1 3RE, UK	3 Subjects, 2 Controls	-	Case series	Dandy-Walker malformation, agenesis of the corpus callosum, microcephaly, rhombic roof dysgenesis and prosencephalic dysgenesis	Fibrocystic liver changes, polydactyly, cleft lip/palate, laterality defects and congenital heart malformations including dextrocardia, shortening and bowing of the long tubular bones and abnormal development of the male genitalia	-	In situ hybridization studies	Direct sequencing via dideoxy chain termination method	-	8q22.1 (c.647delA, p.E216fsX221 and c.A1127C, p.Q376P in MKS3); 17q22 (c.1448_1451dupCAGG duplication, p.T485fsX591 in MKS1)
Duran et al., 2017 [255]	Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia	David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA	3 Subjects, Control cells used	European	Case series	Isolated hydrocephalus	Long narrow chest, markedly shortened long bones, polydactyly and, often, cardiac, gastrointestinal, and genitourinary abnormalities	-	TES	Variant analysis, sanger sequencing	AR	14q24.3 (c.T2A, p.M1K and c.T535C, p.W179R in IFT43); 2p24.1 (IFT121 mutations: c.G1433A, p.R478K; c.C1579T, p.Q527X; c.G932T, p.W311L; c.1501delC, p.Q501Kfs*10)
Edvardson et al., 2010 [256]	Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation	Hebrew University Medical Center, Jerusalem, Israel	13 Subjects, Controls used	Ashkenazi Jewish	Case series	Mid hindbrain malformation, hypotonia, cerebellar ataxia, and developmental delay	Oculomotor apraxia, abnormal breather patterns, retinal degeneration, renal anomalies, ocular colobomas and liver abnormalities	Obstructive	TGS	SNP; array-based hybrid selection; deep sequencing	-	11q12.2 (c.G35T, p.R12L in TMEM216)
Failler et al., 2014 [257]	Mutations of CEP83 cause infantile nephronophthisis and intellectual disability	Laboratory of Inherited Kidney Diseases, 75,015 Paris, France	1,255 Subjects, Controls used	European; Turkish; Latino	Case series	Intellectual disability	Renal malformation, retinitis pigmentosa, intellectual disability, cerebellar ataxia, bone anomalies, liver fibrosis	-	TES	NGS; sanger sequencing	AR	12q22 (CEP83 mutations: c.C121T, p.R41X in exon 3; c.C241T, p.Q81X in exon 4; c.T260T, p.L87P in exon 4; c.335_352del, p.P112_L117del in exon 5; c.C625T, p.R209X in exon 7; c.C1530A, p.C510X in exon 13; c.G1532C, p.R511P in exon 13; c.2007del, p.E669Dfs*14 in exon 17; c.2050_2052del, p.E684del in exon 17; c.2075_2077del, p.Q692del in exon 17)
Kosaki et al., 2004 [258]	Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality	Keio University School of Medicine, Tokyo, Japan	3 Subjects	-	Case study	Isolated hydrocephalus	Situs inversus, micrognathia, ulnar deviation of the fingers with absent distal interphalangeal creases on fingers 2–4, lung abnormalities, and rocker-bottom feet	-	TES	Direct sequencing	AR	-
Mei et al., 2021 [259]	Genetic etiologies associated with infantile hydrocephalus in a Chinese infantile cohort	Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China	110 Subjects, 300 Controls	Chinese	Case series	Isolated hydrocephalus		-	WES	NGS; variant analysis	-	11p15.4 (SBF2 mutations: c.G1171A, p.A391T in exon 12; c.A3877G, p.K1293E in exon 29; c.A3754T, p.S1252C in exon 28; c.A3056T, p.Q1019L in exon 24; c.C5037T, p.R1679R in exon 36; c.C1066T, p.R356X in exon 11; c.G1067T, p.R356L in exon 11; c.A2390G, p.Y797C in exon 20; c.A2813G, p.E938G in exon 23; c.T527G, p.L176W in exon 6; c.A4328C, p.E1443A in exon 32); 10p11.22 (ZEB1 mutations: c.444_461delinsG, p.G150Wfs3 in exon 4; c.479_480delinsA, p.N160Kfs26 in exon 4; c.G2995C, p.E999Q in exon 9); 3p21.31 (c.A465-8C in exon 5 of GNAI2)
Nabhan et al., 2014 [260]	Case Report: Whole-exome analysis of a child with polycystic kidney disease and ventriculomegaly	Kasr Al Ainy School of Medicine, Center of Pediatric Nephrology and Transplantation, Cairo University, Egyptian Group for Orphan Renal Diseases, Cairo, Egypt	1 Subject, 2 Parents	-	Case study	Macrocephaly	Bilateral enlarged and palpable kidneys, systemic hypertension	-	WES	Sanger sequencing, segregation analysis	AR	6p12.3 (c.G3367A, p.G1123S in PKHD1); 17q22 (c.G368A, p.R123Q in MKS1)
Oud et al., 2016 [261]	A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome	Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO-Box 9101, 6500 HB Nijmegen, The Netherlands	4 Subjects, 2 Controls	Turkish	Case study	Absence of septum pellucidum	Genital anomalies, ventral septal defect, renal abnormalities, cystic hygroma, scalp edema ascites, very short tubular bones and polydactyly of hands and feet, and short ribs	-	WES; genotyping	IBD mapping; CNV; Sanger sequencing	-	6p12.1 (c.G358T, p.G120C in ICK)
Rocca et al., 2020 [262]	A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report	University of Padova, Via Giustiniani, Padova, Italy	1 Subject	Moroccan	Case study	Isolated hydrocephalus	Situs inversus, respiratory infections	Communicating	TGS, cytogenetics	NGS; aCGH; CNV	-	17q25.1 (6.9 kb deletion in of DNAI2)
Wallmeier et al., 2019 [263]	De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry	University Children's Hospital Muenster, 48,149 Muenster, Germany	6 Subjects, Controls used	Germany, USA	Case series	Isolated hydrocephalus	Chronic destructive airway disease, and randomization of left/right body asymmetry	Obstructive	WES	Sequencing, unspecified	De novo	17q25.1 (FOXJ1 mutations: c.G901T, p.E301X; c.868_871dup, p.T291Kfs12; c.C826T, p.Q276X; c.967delG, p.E323Sfs10; c.939delC, p.I314Sfs*19)

Array comparative genomic hybridization (aCGH). Autosomal Recessive (AR). Copy number variant (CNV). Identical-By-Descent (IBD). Next generation sequencing (NGS). Single nucleotide polymorphisms (SNP). Targeted exome sequencing (TES). Targeted genome sequencing (TGS). Whole exome sequencing (WES). Whole genome sequencing (WGS)

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