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Re: Disruption of RAB40AL function leads to Martin-Probst syndrome, a
rare X-linked multisystem neurodevelopmental human disorder. Bedoyan JK,
Schaibley VM, Peng W, Bai Y, Mondal K, Shetty AC, Durham M, Micucci JA,
Dhiraaj A, Skidmore JM, Kaplan JB, Skinner C, Schwartz CE, Antonellis A,
Zwick ME, Cavalcoli JD, Li JZ, Martin DM. J Med Genet. 2012 May;49(5):332-
With great interest we have read the article by B...
With great interest we have read the article by Bedoyan and
colleagues. The authors state that disruption of RAB40AL function by a
dinucleotide missense change (chrX:102,079,078-102,079,079AC?GA p.D59G;
hg18) causes Martin-Probst syndrome, a rare X-linked disorder
characterised by deafness, cognitive impairment, short stature and
distinct craniofacial dysmorphisms, among other clinical features.
However, we have reasons to question that conclusion.
We have identified the same dinucleotide missense change in four out
of 446 index patients from families with X-linked intellectual disability
(XLID) by performing high-throughput sequencing of all X chromosome-
specific exons. However, one patient in whom we had identified the p.D59G
substitution also carried a deletion on chromosome 14 that unequivocally
explained the clinical phenotype, which led us to speculate that in this
family the RAB40AL change may not be causative of the phenotype.
Therefore, we carried out segregation analysis in the remaining three
families. One family was not informative for the RAB40L change. In this
family both the clinical phenotype and segregation analyses of
additionally identified variants suggested that this family more likely
carries a pathogenic mutation in another XLID gene. In the remaining two
families, Sanger sequencing confirmed the RAB40AL p.D59G substitution in
the index patients. However, in each of these families, one of the
affected male sibs did not carry the p.D59G substitution. Conversely, the
exome variant server (ESP6500) and dbSNP database report two normal males
who are hemizygous for the p.D59G substitution (dbSNP134 rs145606134). In
yet another XLID family, we have observed a frameshift mutation
(chrX:102192671-102192672 [hg19], ins1bp, p.A143GfsX12) in RAB40AL. In
this family, in a healthy hemizygous male as well as several healthy
homozygous females carried the frameshift variant.
Taken together, these data seem to indicate that the RAB40AL variants
observed are not related to the XLID in our families. Moreover, they
suggest that the RAB40AL p.D59G substitution may not be the cause of
Martin-Probst syndrome but may represent a rare benign variant. While it
is not trivial to prove that a given variant is NOT involved in XLID, the
aggregate evidence presented here suggests that the role of RAB40AL in
XLID and in particular, that of the p.D59G substitution in Martin-Probst
syndrome should be revisited.