Table 3 L1CAM

Bott et al., 2004 [174]

Congenital idiopathic intestinal pseudo-obstruction and hydrocephalus with stenosis of the aqueduct of sylvius

Jeanne de Flandre Hospital, Faculty of Medicine Lille, France

1 Subject

French

Case study

Bilateral nystagmus, convergent strabismus, spastic paraplegia, callosal agenesis

Bilateral adducted thumbs, abdominal distension

Obstructive

-

-

X-linked recessive

Xq28 (G2920T in exon 22 of L1CAM)

Brewer et al., 1996 [175]

X-linked hydrocephalus masquerading as spina bifida and destructive porencephaly in successive generations in one family

Western General Hospital, Edinburgh, UK

1 Subject

-

Case study

Midline cysts, callosal agenesis, cognitive impairment

Asymmetric tetraplegia, low vision, eye movement disorder

Obstructive

-

-

X-linked recessive

Xq28 (Frameshift mutation in L1CAM)

Chidsey et al., 2014 [176]

L1CAM whole gene deletion in a child with L1 syndrome

ARUP Laboratories, Salt Lake City, Utah

1 Subject, 1 Parent

North European

Case study

Absent septum pellucidum

Adducted thumbs with contractures

Obstructive

microarray analysis

SNP analysis

X-linked

Xq28 (62 kb deletion)

Claes et al., 1998 [177]

Hydrocephalus and spastic paraplegia result from a donor splice site mutation (2872 + 1G to A) in the L1CAM gene in a Venezuelan pedigree

Center for Human Genetics, University of Leuven, Belgium

3 Subjects

Venezuela

Case study

Aqueductal stenosis, psychomotor delay, hypotonia, spastic paraplegia

Learning difficulties

Obstructive

cDNA analysis; TGS

Solid-phase approach w/ FITC primer

X-linked

Xq28 (exon 21 microdeletion in L1CAM; G-to-A transition at bp 2872 + 1 of exon 21)

Coucke et al., 1994 [178]

Identification of a 5' splice site mutation in intron 4 of the L1CAM gene in an X-linked hydrocephalus family

University of Antwerp-UIA, Belgium

1 Subject, 1 Control

-

Case study

Aqueductal stenosis, intellectual disability, spastic paresis

Clasped thumbs

-

RT-PCR

Linkage analysis

X-linked

Xq28 (G to A transition at position –5 of the 5’ splice site of intron 4 of L1CAM)

Du et al., 1998 [179]

A silent mutation, C924T (G308G), in the Li CAM gene results in X linked hydrocephalus (HSAS)

J C Self Research Institute of Human Genetics, Greenwood Genetic Center, SC 29646, USA

1 Subject, 1 Family member

-

Case study

Callosal agenesis, intellectual disability, spastic paraplegia

Clenched fingers, overlapping digits

Obstructive

TES

REF

X-linked

Xq28 (c.C924T, p.G308G silent mutation in exon 8 of L1CAM)

Du et al., 1998 [180]

Multiple exon screening using restriction endonuclease fingerprinting (REF): detection of six novel mutations in the L1 cell adhesion molecule (L1CAM) gene

J C Self Research Institute of Human Genetics, Greenwood Genetic Center, SC 29646, USA

5 Subjects, 200 Controls

-

Case series

Intellectual disability

Adducted thumbs with contractures, aphasia

-

TGS

SSCP, REF

X-linked, De novo

Xq28 (6 novel mutations in the L1CAM gene: intron 7 (G to A base substitution at position 807–6 at the 3 ́ splice site); intron 11 (G to A transition at position 1379 + 5 within the 5 ́ splice site); intron 10 (A to T base change at position 1268–2 of the 3 ́ splice site); within exons 16–18 (c.G2092A, p.G698R); exon 16 (c.C2072A, p.A691D); exon 21 (c.T2804C, p.L935P))

Du et al., 1998 [181]

Somatic and germ line mosaicism and mutation origin for a mutation in the L1 gene in a family with X-linked hydrocephalus

J C Self Research Institute of Human Genetics, Greenwood Genetic Center, SC 29646, USA

5 Subjects, 200 Controls

-

Case study

Intellectual disability

Adducted thumbs with contractures, aphasia

Obstructive

TGS

SSCP

X-linked

Xq28 (G to A nucleotide change at the first position of intron 10 of L1CAM)

Ferese et al., 2016 [182]

A New Splicing Mutation in the L1CAM Gene Responsible for X-Linked Hydrocephalus (HSAS)

Localita' Camerelle, Pozzilli, Italy

1 Subject, 1 Control

-

Case study

Aqueductal stenosis, thinned cerebral parenchyma, lissencephaly, corpus callosum agenesis,

Adducted thumbs, dysmorphic facial features

Obstructive

TGS

Direct sequencing

X-linked recessive

Xq28 (Intron 10 in L1CAM hemizygous for c.1267 + 5delG; loss of exon 10 via abnormal splicing)

Fernandez et al., 2012 ([183]

Association of X-linked hydrocephalus and Hirschsprung disease: report of a new patient with a mutation in the L1CAM gene

Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

1 Subject

-

Case study

Bilateral spastic tetraparesis, psychomotor growth delay

Cephalo-pelvic dystocia, hirschsprung’s disease

Obstructive

TES

-

X-linked

Xq28 (c.2092G > A, p.G698R in exon 16 of L1CAM)

Finckh et al., 2000 [184]

Spectrum and Detection Rate of L1CAM Mutations in Isolated and Familial Cases with Clinically Suspected L1-Disease

University Hospital Eppendorf, University of Hamburg, Hamburg, Germany

153 Subjects, 100 controls

-

Case series

Spastic paraplegia, intellectual disability, agenesis, hypoplasia of corpus callosum

Adducted thumbs with contractures, cleft palate, heart malformation, esophageal atresia, club feet

-

TES

SSCP

X-linked, De novo

Xq28 (L1CAM mutations)

Fransen et al., 1994 [185]

X-linked hydrocephalus and MASA syndrome present in one family are due to a single missense mutation in exon 28 of the L1CAM gene

University of Antwerp-UIA, Belgium

1 Subject

-

Case study

Extreme macrocephaly, severe spasticity, and intellectual disability

Shuffling gait, adducted thumbs

-

Southern Blotting

SSCP analysis

X-linked

Xq28 (c.C3581T, p. S1194L in exon 28 of L1CAM)

Gigarel et al., 2004 [186]

Single cell co-amplification of polymorphic markers for the indirect preimplantation genetic diagnosis of hemophilia A, X-linked adrenoleukodystrophy, X-linked hydrocephalus and incontinentia pigmenti loci on Xq28

Hôpital Necker Enfants Malades, 75,015 Paris, France

10 Subjects, Controls used

-

Case Series

Isolated hydrocephalus

Hemophilia a

-

TGS

Microsatellite marker assay

X-linked recessive

Xq28 (2872 + 1 G to A mutation in intron 21 of L1CAM)

Graf et al., 2000 [187]

Diffusion-weighted magnetic resonance imaging in boys with neural cell adhesion molecule L1 mutations and congenital hydrocephalus

University of Washington School of Medicine, Seattle, USA

5 Subjects, 1 Control

Italian

Case series

Agenesis of the corpus callosum, diffuse cerebral dysplasia, decreased white matter, small posterior fossa, Chiari I malformation

Developmental delay

Obstructive

TES

REF

X-linked

Xq28 (14 bp deletion in exon 11, 1 bp deletion in exon 10, p.C466G in exon 5, and p.R184W in L1CAM)

Gregory et al., 2019 [188]

Mutations in MAGEL2 and L1CAM Are Associated with Congenital Hypopituitarism and Arthrogryposis

UCL Great Ormond Street Institute of Child Health, London, United Kingdom

5 subjects, Controls used

European, Chile, Afro-Caribbean

Case series

Hypotonia, bulky tectum, white matter loss, thin corpus callosum

Bilateral radial clubbed hands, plagiocephaly, distal arthrogryposis with adducted thumbs, flexion deformities, growth hormone deficiency, ventricular septal defect, severe obstructive sleep apnea, global developmental delay, right hip subluxation, scoliosis, bilateral astigmatism, visual impairment

Communicating

WES; chromosome microarray

Sangar Sequencing; Human embryonic expression analysis; Ingenuity Variant analysis

X-linked

Xq28 (c.G1354A, p.G452R in L1CAM)

Griseri et al., 2009 [189]

Complex pathogenesis of Hirschsprung's disease in a patient with hydrocephalus, vesico-ureteral reflux and a balanced translocation t(3;17)(p12;q11)

Laboratory Molecular Genetics and Cytogenetics, Genova, Italy

1 Subject, 1 Control

-

Case Study

Intellectual disability, bilateral spastic paraplegia

Adducted thumbs, vesico-ureteral reflux, developmental delay

-

TGS

-

X-linked, De novo

Xq28 (c.2265delC, p.P756Lfs95X in exon 18 of L1CAM); haploinsufficiency of MYO18A/TIAF1 genes involved in a balanced translocation (3;17)(p12;q21)

Gu et al., 1996 [190]

Five novel mutations in the L1CAM gene in families with X linked hydrocephalus

Institut fur Humangenetik, Medizinische Universitat zu Lubeck, Germany

5 Subjects

-

Case series

Intellectual disability, spastic paresis, complex brain malformation with agenesis of the corpus callosum and fusion of the

Thalamus

Deafness,

Adducted thumbs, global physical delay, cleft lip and palate

-

TES

SSCP, HA

X-linked, De novo

Xq28 (mutations in exon 1, 6, 7, and 8 of L1CAM)

Guo et al., 2020 [191]

A novel nonsense mutation in the L1CAM gene responsible for X-linked congenital hydrocephalus

Xiangya Hospital, Central South University, Changsha, Hunan, China

1 Subject

Chinese

Case study

Agenesis of the corpus callosum, vermis hypoplasia and enlargement of the quadrigeminal plate, aqueductal stenosis

Tower-shaped skull, contractions of both thumbs

Obstructive

WES; chromosomal karyotyping; chromosomal microarray analysis

Sangar Sequencing; Variant segregation analysis

X-linked recessive

Xq28 (c.C2865A in exon 21 of L1CAM)

Hubner et al., 2004 [192]

Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing

University Hospital Eppendorf, Hamburg, Germany

7 Subjects, 50 Controls

-

Case series

Intellectual disability, hypoplastic or absent corticospinal tract, callosal agenesis, spastic paraparesis, aqueductal stenosis

Aphasia, shuffling gait, adducted thumbs

-

TGS

SSCP analysis

X-linked

Xq28 (Intronic L1CAM sequence variants: c.523 + 5G > A; c.1123 + 1G > A; c.1547-13delC in intron 12; c.3323-17dupG; c.3457 + 3A > T; c.3457 + 18C > T; and c.523 + 12C > T)

Jouet et al., 1994 (79)

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene

University of Cambridge, Addenbrooke's Hospital, UK

6 Subjects

-

Case series

Agenesis of the corpus callosum; agenesis of the septum pellucidum; fusion of thalami and hypoplasia of the corticospinal tract, aqueductal stenosis, spastic diplegia

Adducted thumbs

Obstructive

TES

SSCP, HA

X-linked

Xq28 (L1 gene mutations: 2 bp deletion in exon 26; single nucleotide deletion in exon 22; p.H210Q in second Ig domain; G to A nucleotide change, p.Q184R in exon 6; C to T mutation in exon 12 that introduces a stop codon at amino acid position 485; G to A mutation in exon 11 that changes a Gly to Arg residue)

Jouet et al., 1995 [193]

Gene analysis of L1 neural cell adhesion molecule in prenatal diagnosis of hydrocephalus

Addenbrooke's Hospital, Cambridge, UK

2 Subjects

-

Case series

Intellectual disability, spastic paraparesis

Developmental delay, adducted thumbs

-

TGS

SSCP, Direct sequencing

X-linked, De novo

Xq28 (g + 1- > t in the intron 1 donor splice site and 1 bp deletion in exon 22 of L1CAM)

Jouet et al., 1996 [194]

Discordant segregation of Xq28 markers and a mutation in the L1 gene in a family with X linked hydrocephalus

University of Cambridge, UK

19 Subjects

-

Case study

Intellectual disability, and spastic paraplegia type I

Aphasia, shuffling gait, adducted thumbs

-

TES

SSCP; HA

X-linked

Xq28 (deletion of a single adenosine at position 3088 in exon 23 of L1CAM)

Kanemura et al., 2006 [195]

Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus

Osaka National Hospital, Osaka, Japan

96 Subjects, 7 Controls

Japanese

Case series

Corpus callosum agenesis, vermis hypoplasia, epilepsy, spastic paraplegia

Bilateral adducted thumbs, developmental delay, elevated diaphragm

-

TGS

Direct sequencing

X-linked, De novo

Xq28 (L1CAM mutations: exon 1 (c.A74T, p.E25V); exon 5 (c.474delC, p.fs158); exon 6 (c.665delA, p.fs222); exon 8 (c.G935A, p.C312Y; c.C870A, p.Y290X); exon 11 (c.T1373A, p.V458D); exon 16 (c.G2065T, p.V689F); exon 18 (c.G2254A, p.V752M); exon 20 (c.A2578T, p.K860X; c.C2701T, p.R901X); exon 21 (c.T2858G, p.L953R); exon 22 (c.2885delG, p.fs962; c.G3022T, p.E1008X); intron 2 (c.92-1gA); intron 3 (c.197 + 1gA); intron 4 (400 + 1gA); intron 6 (c.694 + 5gA); intron 13 (c.1704-1gA); intron 14 (c.1829-1gC; c.1829-12del19bp); intron 15 (c.1940–21 ~ 1940–6); intron 18 (c.2431 + 1delGT); intron 21 (c.2872 + 1gA); intron 22 (c.3047-1gA))

Kong et al., 2019 [196]

A new frameshift mutation in L1CAM producing X-linked hydrocephalus

Sichuan Provincial Hospital for Women and Children, Chengdu, China

1 Subject, 2 Parents

-

Case study

Callosal agenesis and lissencephaly

-

-

WES

Sangar Sequencing

X-linked recessive

Xq28 (c.2491delG (p.V831fs) in exon 19 of L1CAM)

Liebau et al., 2007 [197]

L1CAM mutation in a boy with hydrocephalus and duplex kidneys

University Hospital of Freiburg, Mathildenstrasse 1, Freiburg, Germany

1 Subject

-

Case study

Tower-shaped skull, corpus callosum agenesis, Intellectual disability, microcephaly, strabismus, neurogenic bladder dysfunction, spasticity

Bilateral duplex kidneys and ureters, unilateral mega-ureter, adducted thumbs

-

TGS

SSCP

X-linked

Xq28 (c.2431 + 2delTG at the beginning of intron 18 of L1CAM)

Limbrick et al., 2017 [198]

Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus

Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America

20 Subjects, 51 Controls

Caucasian, Black, Asian

Case series

Isolated hydrocephalus

Obstructive

Chromosomal microarrays, TGS

-

-

Xq28 (G847X mutation in L1CAM); 1q25.2 anomaly; 11q24.2 anomaly

MacFarlane et al., 1997 [199]

Nine novel L1 CAM mutations in families with X linked hydrocephalus

University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, UK

20 Subjects, 56 Controls

-

Case series

Intellectual disability, spastic paraplegia, corpus callosum agenesis, absence of the cortical spinal tract

Adducted thumbs

Obstructive

TES

SSCP; SNuPE

X-linked

Xq28 (L1CAM: exon 6 (c.G551A, p.R184Q); exon 11 (microdeletion); exon 13 (c.C1672T, p.R558X); exon 18 (c.A2351G, p.Y784C; c.A2374GG, p.fs791(+ 25); c.G2262A, p.W754X); exon 20 (c.C2701T, p.R901X); exon 21 (microdeletion); intron 7 (c.G(807–6)A); intron 24 (c.T(3322 + 2)C))

Marin et al., 2015 [200]

Three cases with L1 syndrome and two novel mutations in the L1CAM gene

Hospital Universitario Puerta del Mar, Cádiz, Spain

3 subjects

-

Case series

Corpus callosum agenesis, microcephaly, spastic paraplegia,

Developmental delay, bilaterally flexed adducted thumbs, bilateral clinodactyly of the fifth finger

-

TES

Sangar Sequencing

X-Linked recessive, De novo

Xq28 (L1CAM mutations: c.A1754C, p.D585A; c.C3478T, p.Q1160X; c.G353112A in exon 27)

Marx et al., 2012 [201]

Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus

Institute of Anatomy and Cell Biology, Center for Neurosciences, University of Freiburg, Freiburg, Germany

3 Subjects, Control cells used

-

Case study

Aqueductal stenosis

Adducted thumbs

Obstructive

TGS

Direct sequencing

X-linked

Xq28 (L1CAM mutations: c.C99232T in intron 8; c.G1906C, p.W635C in exon 15; c.G2302A, p.V768I in exon 18)

Michaelis et al., 1998 [202]

The site of a missense mutation in the extracellular Ig or FN domains of L1CAM influences infant mortality and the severity of X linked hydrocephalus

Center for Molecular Studies, J C Self Research Institute, Greenwood Genetic Center, SC 29646, USA

7 Subjects, Controls used

-

Case series

Intellectual disability, spasticity, aqueductal stenosis

Adducted thumbs

Obstructive

TES

SSCP, REF

X-linked

Xq28 (missense mutations in the extracellular Ig or FN domains of L1CAM)

Nakakimura et al., 2008 [203]

Hirschsprung's disease, acrocallosal syndrome, and congenital hydrocephalus: report of 2 patients and literature review

Hokkaido University Graduate School of Medicine, Sapporo, Japan

2 Subjects

-

Case series

Callosal body agenesis, spastic paralysis, and porencephaly

Bilateral inferior limbs, and bilateral thumb adduction, polydactyly

Obstructive

TGS

Direct sequencing

X-linked

Xq28 (c.T3140C, p.V31A in exon 3 of L1CAM)

Okamoto et al., 1997 [204]

Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM

Osaka Medical Centre, Japan

1 Subject

Japanese

Case study

Intellectual disability, spastic quadriplegia, agenesis of the corpus callosum and septum

Pellucidum, irregular ventricular wall, hypoplastic white matter, cerebellar hypoplasia, and

Fusion of the thalami

Cleft palate, micrognathia, abdominal distension, bilateral adducted thumbs, and flexion contractures of the fingers

-

TES

Fluorescent dideoxy terminator method

X-linked, De novo

Xq28 (2 bp deletion in exon 18 of L1CAM)

Okamoto et al., 2004 [205]

Hydrocephalus and Hirschsprung’s disease with a mutation of L1CAM

Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka, Japan

3 Subjects

Canadian, Spanish

Case series

Cerebellar hypoplasia, corpus callosal dysgenesis, thalami fusion, decreased white matter, aqueductal stenosis, intellectual disability, spastic paraparesis

Hirschsprung’s disease, bilateral adducted thumbs, flexion contracture of fingers, aphasia

Obstructive

TGS

Direct sequencing

X-linked recessive

Xq28 (Intron 15 mutation and p.Q992X in exon 22 of L1CAM)

Panayi et al., 2005 [206]

Prenatal diagnosis in a family with X-linked hydrocephalus

National Taiwan University Hospital, Taipei, Republic of China

1 Subject

-

Case study

Aqueductal stenosis,

Underdevelopment of brain tissue, spastic quadriplegia, seizures, and psychomotor retardation

Aphasia

Obstructive

TES

Cycle sequencing, SSCP, HA

X-linked, De novo

Xq28 (deletion of exon 2 and 6 in L1CAM)

Parisi et al., 2002 [207]

Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?

University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington 98,105, USA

1 Subject, 1 Control

-

Case study

Macrocephaly, aqueductal stenosis, corpus callosum agenesis

Bilateral adducted thumbs and index fingers, bilateral inguinal hernias, hirschsprung's disease, developmental delay, micropenis, small descended right testis, cryptorchid left testis, upgoing toes, limb spasticity, strabismus, amblyopia

Obstructive

TGS

REF, SSCP

X-linked

Xq28 (c.G2254A, p. V752M in exon 18 of L1CAM)

Pomili et al., 2000 [208]

MASA syndrome: ultrasonographic evidence in a male fetus

University Hospital, Perugia, Italy

1 Subject

Italian

Case study

Intellectual disability, spasticity of the lower limbs, callosal hypoplasia

Colorblindness, bilaterally adduced thumbs

-

TGS

DGGE; direct sequencing

X-linked

Xq28 (G > A base substitution 12 bp upstream from the intron/exon boundary of exon 27 in L1CAM gene)

Rehnberg et al., 2010 [209]

Novel L1CAMSplice Site Mutation in a Young Male with L1 Syndrome

Linköping University, University Hospital, Linköping, Sweden

1 Subject, 3 Family Members

Swedish

Case study

Global hypotonia, intellectual disability, spastic paraplegia

Bilateral adducted thumbs

-

TGS

Dideoxynucleotide sequencing

X-linked, De novo

Xq28 (c.G3458-1C in L1CAM)

Rodríguez Criado et al., 2003 [210]

X-linked hydrocephalus: another two families with an L1 mutation

Unidad de Dismorfología, H.I.U.V. Rocío, Sevilla, Spain

3 Subjects

-

Case series

Intellectual disability

Aphasia, shuffling gait, and adducted thumbs

Obstructive

TGS

DGGE; REF; direct sequencing

X-linked, De novo

Xq28 (c.C196T, p.Q66X in exon 3 of L1CAM; 1267 + 1G > A in intron 10 of L1CAM)

Ruiz et al., 1995 [211]

Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS

University of Leuven, Belgium

3 Subjects

-

Case–Control

Spastic paresis, intellectual disability, aqueductal stenosis

Adducted thumbs

Obstructive

TGS

Solid-phase approach w/ FITC primer; Dot Blot Assay

X-linked

Xq28 (15 bp deletion was found at coding position 97 of the cDNA; 12 bp deletion at bp3551; c.T875C; insertion of a cytosine at nucleotide position 3806 within the 3' untranslated region; exons 4,5,6 (c.T556G, p. I179S); exons 8,9,10 (c.G1128A, p.G370R))

Saugier-Veber et al., 1998 [212]

Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis

Laboratoire de Génétique Moléculaire, CHU de Rouen, France

13 Subjects, 100 Controls

French

Case series

Intellectual disability, spastic paraplegia

Aphasia, shuffling gait, adducted thumbs, hirschsprung’s disease

Obstructive

TGS; genotyping

FAMA; ACRS

X-linked, De novo

Xq28 (L1CAM nucleotide changes: c.365delC, p.FS122 in exon 4; c.400 + 5G > A, p.FS108 in intron 4; c.T656C, p. I219T in exon 6; c.T1003C, p. W335R in exon 9; c.C1156T, p. R386C in exon 10; c.C1417T, p. R473C in exon 12; c.C2572T, p. Q858SX in exon 20; c.2872 + 1G > A in intron 21; c.C3671T, p. S1224L in exon 28; c.3323-30G > A in intron 24)

Senat et al., 2001 [213]

Prenatal diagnosis of hydrocephalus-stenosis of the aqueduct of Sylvius by ultrasound in the first trimester of pregnancy. Report of two cases

CHI Poissy, France

2 Subjects

Caucasian

Case study

Corpus callosum agenesis, hypoplasia of pyramidal tract, spasticity, intellectual disability

Adducted thumbs

Obstructive

TGS

FAMA

De novo

Xq28 (p.Y589H in exon 14 of L1CAM)

Serikawa et al., 2014 [214]

Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene

Niigata University Medical and Dental Hospital, Niigata, Japan

4 Subjects, 2 Parents

Japanese

Case study

Cortex thinning, cerebral palsy, intellectual disability, corpus callosum agenesis, aqueductal stenosis

Bilateral adducted thumbs

Obstructive

TGS

Sanger Sequencing

X-linked

Xq28 (c.C924T, p. G308G silent mutation in exon 8 of L1CAM)

Silan et al., 2005 [215]

A novel L1CAM mutation with L1 spectrum disorders

Abant Izzet Baysal University, Duzce School of Medicine, Duzce, Turkey

14 Subjects

Turkish

Case series

Corpus callosum agenesis, intellectual disability, spastic quadriplegia

Bilateral adducted thumbs

-

-

-

X-linked

Xq28 (c.C1375T, Q459X in exon 11 of L1CAM)

Stowe et al., 2018 [216]

Clinical Reasoning: Ventriculomegaly detected on 20-week anatomic fetal ultrasound

Baylor College of Medicine, Texas Children's Hospital, Houston

1 Subject

-

Case study

Aqueductal stenosis, diencephalic fusion, and brainstem dysplasia

Fisted thumbs

Obstructive

WES

Trio-based WES

X-linked, De novo

Xq28 (c.1703 + 5G > A in L1CAM)

Sullivan et al., 2020 [128]

Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus

Yale School of Medicine, New Haven, Connecticut

475 Subjects

European, African American, south Asian

Case series

Hypotonia, cerebral palsy, epilepsy, white-matter hypoplasia, agenesis of the corpus callosum, macrocephaly

Bilateral adducted thumbs, skeletal abnormalities

Obstructive

WES

Sanger sequencing

X-linked, De novo

Xq28 (L1CAM mutations: p.W460C; p.W635R; c.1828 + 1G > A (localizing to intron 15); c.1546 + 1G > T (located in intron 13); p.E304X; p.V788F; c.806 + 1G > C (positioned in intron 8))

Sztriha et al., 2000 [217]

Novel missense mutation in the L1 gene in a child with corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus

Faculty of Medicine and Health Sciences, United Arab Emirates University

1 Subject, 1 Parent, 1 Control

Arabic

Case study

Corpus callosum agenesis, intellectual disability, spastic paraparesis

Adducted thumbs

Communicating

TES

DGGE analysis

X-linked

Xq28 (c.G604T in exon 6 of L1CAM)

Sztriha et al., 2002 [218]

X-linked hydrocephalus: a novel missense mutation in the L1CAM gene

Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain

1 Subject

Pakistani

Case study

Spastic diplegia, intellectual disability, multiple small gyri, markedly reduced white matter volume, agenesis of the corpus callosum, and lack of cleavage of the thalami

Adducted thumbs

Obstructive

-

-

X-linked

Xq28 (c.G1243C, p.A415P in exon 10 of L1CAM)

Takahashi et al., 1997 [219]

L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling

Asahikawa Medical College, Nishikagura, Japan

1 Subject, 2 Parents, 2 Sisters

Japanese

Case study

Intellectual disability, spastic quadriplegia

Bilateral adducted thumbs

Obstructive

TES

-

X-linked

Xq28 (1 bp deletion in exon 22 of L1CAM resulting in a premature stop codon)

Takechi et al., 1996 [220]

A deletion of five nucleotides in the L1CAM gene in a Japanese family with X-linked hydrocephalus

National Institute of Neuroscience, Tokyo, Japan

2 Subjects, 1 Sister

Japanese

Case study

Aqueduct of Sylvius, mental retardation, and spastic paraparesis

Bilateral clasped thumbs

-

TES

Dideoxy plasmid-based sequencing

X-linked

Xq28 (5 bp deletion in exon 8 of L1CAM)

Takenouchi et al., 2011 [221]

Hydrocephalus with Hirschsprung disease: severe end of X-linked hydrocephalus spectrum

Keio University School of Medicine, Tokyo, Japan

1 Subject

Japanese

Case study

Aqueductal stenosis, hypoplasia of the corpus callosum

Hirschsprung disease, frontal bossing, adducted thumbs

Obstructive

TGS

Mutation analysis, unspecified

X-linked, De novo

Xq28 (c.C61T, p.Q21X in exon 1 of L1CAM)

Tegay et al., 2007 [222]

Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus

Stony Brook University Hospital, Stony Brook, New York, USA

1 Subject, Mother, Grandmother, 1 Control

Northern European

Case study

Hypotonia

Bilateral adducted thumbs, hirschsprung disease

Obstructive

WGS

GeneDX, microdeletion

X-linked

Xq28 (32.7 kb deletion and 90 bp insertion at the L1CAM-AVPR2 junction sequence (from L1CAM intron1 to AVPR2 exon2))

Van Camp et al., 1993 [223]

A duplication in the L1CAM gene associated with X-linked hydrocephalus

University of Antwerp-UIA, Belgium

25 Subjects, Controls used

The Netherlands, United Kingdom, USA, Israel, Germany, Hungary, Belgium

Case series

Stenosis of the aqueduct of Sylvius, intellectual disability, spastic para paresis of the lower extremities, aplasia or hypoplasia of the corpus callosum

Bilateral adducted thumbs

-

Southern Blotting

-

X-linked recessive

Xq28 (1.3 kb duplication in L1CAM)

Verhagen et al., 1998 [224]

Familial congenital hydrocephalus and aqueduct stenosis with probably autosomal dominant inheritance and variable expression

Canisius Wilhelmina Hospital, Nijmegen, Netherlands

12 Subjects

-

Case series

Septum pellucidum cavitation, aqueductal stenosis

Obstructive

TES

-

AD

No mutations in L1CAM

Vits et al., 1994 [225]

MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM

University of Antwerp, Belgium

8 Subjects, 50 Controls

United States, the Netherlands, Mexico, UK, Germany

Case series

Intellectual disability

Adducted thumbs, shuffling gait, aphasia

-

TGS

SSCP

X-linked

Xq28 (p.D598N in exon 14 and p.H210Q in exon 6 of L1CAM)

Vos et el., 2010 [226]

Genotype–phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis

University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

367 Subjects, 3 Controls

Various

Case–Control

Aqueductal stenosis, intellectual disability, callosal agenesis

Adducted thumbs, shuffling gait, aphasia

Obstructive

TES

DGGE; direct sequencing; MLPA

X-linked recessive

Xq28 (L1CAM mutations: 23 missense mutations; 3 in-frame deletions/duplications; 18 splice site mutations; 14 nonsense mutations; 8 frame-shift mutations; 1 duplication of exons 2–10; 1 deletion of the entire gene; c.C645T within exon 6 of L1CAM)

Wilson et al., 2009 [227]

Prenatal identification of a novel R937P L1CAM missense mutation

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

2 Subjects

Caucasian

Case study

Aqueductal stenosis, agenesis or hypoplasia of the corpus callosum and corticospinal tracts, intellectual disability, spastic paraplegia

Adducted thumbs, short femurs, right clubbed foot

Obstructive

TGS

bidirectional DNA sequencing

X-linked

Xq28 (c.G2809C, p.R937P in exon 21 of L1CAM)

Xie et al., 2018 [228]

Two novel pathogenic variants of L1CAM gene in two fetuses with isolated X-linked hydrocephaly: A case report

Guangxi Maternal and Child Health Hospital, Nanning, Guangxi, P.R. China

2 Subjects, 4 Parents, 100 Controls

Chinese

Case–Control

Isolated hydrocephalus

-

TES

Sanger sequencing

X-linked

Xq28 (c.C998T, p.P333L and c.G2362T, p.V788F in L1CAM)

Yamasaki et al., 2011 [229]

Prenatal molecular diagnosis of a severe type of L1 syndrome (X-linked hydrocephalus)

Osaka National Hospital, National Hospital Organization, Osaka City, Japan

14 Subjects

Japanese

Case series

Intellectual disability, spastic paraplegia

Adducted thumbs, shuffling gait, aphasia

-

TGS

Direct sequencing

X-linked

Xq28 (L1CAM mutations: c.G1829-1C 1 bp downstream from the 5′ of intron 14; ACC (817–819) nucleotide deletion in exon 8, deletion of T at amino acid position 273; c.C1146A, p.Y382X in exon 10)