Mandibuloacral Dysplasia Caused by LMNA Mutations and Uniparental Disomy.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. Hutchinson-Gilford Progeria Syndrome (HGPS) is characterized by the clinical features of accelerated aging in childhood. Both MAD and HGPS can be caused by mutations in the LMNA gene. In this study, we describe a 2-year-old boy with overlapping features of MAD and HGPS. Mutation analysis of the LMNA gene revealed a homozygous missense change, p.M540T, while only the mother carries the mutation. Uniparental disomy (UPD) analysis for chromosome 1 showed the presence of maternal UPD. Markers in the 1q21.3-q22 region flanking the LMNA locus were isodisomic, while markers in the short arm and distal 1q region were heterodisomic. These results suggest that nondisjunction in maternal meiosis followed by loss of the paternal chromosome 1 during trisomy rescue might result in the UPD1 and homozygosity for the p.M540T mutation observed in this patient.

Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants. In an expanded case set, NAT2 continued to show significant overtransmission of an allele to the fetus, with a final P value of .00003. There was an interaction between maternal smoking and fetal inheritance of a GSTT1-null deletion, seen in both the Danish (P=.03) and Iowan (P=.002) studies, with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples, involving independent populations, that provided substantial power and a framework for future studies that could identify a susceptible population for preventive health care.