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. 2015 Jan;23(1):49-53.
doi: 10.1038/ejhg.2014.60. Epub 2014 Apr 23.

Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome

François Cartault  1 , Patrick Munier  2 , Marie-Line Jacquemont  3 , Jeannine Vellayoudom  2 , Bérénice Doray  2 , Christine Payet  2 , Hanitra Randrianaivo  3 , Jean-Marc Laville  4 , Arnold Munnich  5 , Valérie Cormier-Daire  5
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Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome

François Cartault et al. Eur J Hum Genet. 2015 Jan.

Abstract

First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.

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Figures

Figure 1
Figure 1
(a) Left: the female proband at 2 years of age, with round, flattened midface, prominent forehead, circles under eyes and microstomia, right: paternal uncle at 29 years of age with very small stature (122 cm) and obesity (BMI: 45.9). (b) Left: hand at 28 months of age with short fingers, right: X-Rays showing advanced carpal ossification (3½ years contrasting with the chronological age of 28 months), delta phalanx and proximal radioulnar synostosis. (c) Clinically unstable knee joint (left) confirmed by the femorotibial misalignment (right). (d) X-rays showing Swedish key appearance of the proximal femur (left) and radioulnar synostosis (right). (e) Pedigree of the family studied by exome sequencing. (f) Chromatograms showing the mutation in B4GALT7 gene in control (wild type), affected (homozygous patients) and carrier (heterozygous parents) cases.
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