Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

On the basis of these results, it is concluded that P25L is a benign variant of the VHL protein and individuals carrying this variant should not be required to undergo screening for VHL manifestations.

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Mutations in ABCC9 have been implicated in the development of Cantu syndrome, Brugada syndrome and isolated dilated cardiomyopathy (DCM). ABCC9 codes for the SUR2A subunit of the cardiac K(ATP) channel. Missense mutations are implicated in the development of Cantu as gain of function effects, but a null mutation has been reported in the literature as causing isolated DCM. We report a large family with an ABCC9 mutation. The female proband presented at age 63 with severe bradycardia requiring a pacemaker, and was diagnosed at age 67 with DCM. A heterozygous null mutation in ABCC9, c.169C >T (p. Gln57X) in exon 2 was discovered and was reported in 2009 as presumed pathogenic. Her obligate carrier brother had severe DCM in his mid 50’s requiring cardiac transplantation. Her obligate carrier sister is reported to have a pacemaker in her 60’s with no DCM. In the subsequent generation, a male with the mutation at age 46 had a normal LV size and function, with a reported mild concentric LVH. Four other mutation carriers (ages 32, 40, 42 and 59) have no echocardiographic evidence of DCM. Although non-penetrance and variable expressivity could explain the large number of unaffected mutation carriers in the family, it remains unclear if this ABCC9 mutation is responsible for the DCM in this family. Despite mutations in this gene being reported in 2004 as causing DCM, there are few subsequent reports of affected families, and no reports of familial segregation. This family illustrates the difficulty in interpreting molecular results when literature is limited and published before more stringent criteria for pathogenicity were established. The importance of careful family follow up of purported genetic mutations cannot be overstated. A critical literature review and correlating familial genotype and phenotype information should be performed when interpreting molecular genetic test results.