Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis.
OBJECTIVE
To develop a comprehensive mutation analysis system with a high rate of detection, to develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and to look for genotype-phenotype correlations in the X-linked recessive disorder, L1 syndrome.


METHODS
DNA from 367 referred patients was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences and for large duplications. Clinical data for 106 patients were collected and used for statistical analysis.


RESULTS
68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 8%; p=0.02).


CONCLUSIONS
We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.
Vos
Yvonne J
YJ
Department of Genetics, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. y.j.vos@medgen.umcg.nl
de Walle
Hermien E K
HE
Bos
Krista K
KK
Stegeman
Jenneke A
JA
Ten Berge
Annelies M
AM
Bruining
Martijn
M
van Maarle
Merel C
MC
Elting
Mariet W
MW
den Hollander
Nicolette S
NS
Hamel
Ben
B
Fortuna
Ana Maria
AM
Sunde
Lone E M
LE
Stolte-Dijkstra
Irene
I
Schrander-Stumpel
Connie T R M
CT
Hofstra
Robert M W
RM
D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D056726:Genetic Association Studies; D005817:Genetic Counseling / Q000379:methods*; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009030:Mosaicism; D039842:Neural Cell Adhesion Molecule L1 / Q000032:analysis / Q000235:genetics*; D017410:Practice Guidelines as Topic; D013577:Syndrome
D039842:Neural Cell Adhesion Molecule L1