A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance.

Orphanet Journal of Rare Diseases
Bassam R AliLihadh Al-Gazali

Abstract

We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia. We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.

References

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Citations

Jun 19, 2013·Orphanet Journal of Rare Diseases·Nadia A AkawiLihadh Al-Gazali
Aug 2, 2013·Osteoporosis International : a Journal Established As Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA·S LazarusE L Duncan
Nov 2, 2013·Trends in Genetics : TIG·Luciana Musante, H Hilger Ropers
Jan 1, 2014·Human Genome Variation·Salma Ben-SalemLihadh Al-Gazali
Nov 13, 2012·European Journal of Medical Genetics·Diana M WalshEamonn R Maher
Jul 16, 2015·American Journal of Medical Genetics. Part a·Sanjin TunovicAnne M Slavotinek
Feb 26, 2015·Clinical Dysmorphology·Kadri KaraerTania Attié-Bitach
Nov 14, 2014·Journal of Human Genetics·Milena SimioniVera Lúcia Gil-da-Silva-Lopes
Aug 4, 2016·Scientific Reports·Sarah BianchiRichard A Kammerer
Oct 22, 2016·Trends in Cell Biology·Mu HeKathryn V Anderson
Nov 6, 2018·Human Molecular Genetics·Filomena MassaManuela Morleo
Oct 23, 2019·American Journal of Medical Genetics. Part a·Steven D KleinJulian A Martinez-Agosto
Apr 30, 2020·The Journal of Cell Biology·Petra PejskovaLukas Cajanek
Jan 1, 2015·Human Genome Variation·Duna BarakehFowzan S Alkuraya
Apr 24, 2021·Asian Journal of Psychiatry·Dhruva IthalSanjeev Jain

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Methods Mentioned

BETA
exome sequencing

Software Mentioned

HomozygosityMapper
GATK

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