Implications of a Chr7q21.11 microdeletion and the role of the PCLO gene in developmental delay

We report here a 4-year-old boy with global developmental delay who was referred for karyotyping and fragile X studies. A small interstitial deletion on chromosome 7 at band 7q21 was detected in all cells examined. Subsequent molecular karyotype analysis gave the more detailed result of a 6.3 Mb heterozygous deletion involving the interstitial chromosome region 7q21.11. In this relatively gene-poor region, the presynaptic cytomatrix protein, Piccolo [PCLO] gene appears to be the most likely candidate for copy number loss leading to a clinical phenotype. G-banded chromosome analysis of the parents showed this deletion was inherited from the father. Molecular karyotype analysis of the father's genome confirmed that it was the same deletion as that seen in the son; however, the father did not share the severity of his son's phenotype. This cytogenetically-visible deletion may represent another example of a chromosomal rearrangement conferring a variable phenotype on different family members

Clinical outcomes and counseling issues regarding partial trisomy of terminal Xp in a child with developmental delay

Female carriers of balanced translocations involving an X chromosome and an autosome present genetic councelling challenges. This is in view of the number of possible meiotic outcomes, but also due to the impact of X chromosome-localised genes that are no longer subject to gene silencing through the X chromosome inactivation centre. We present a case where delineation of the extent of X chromosome-localised genes on the derivative autosome using molecular karyotyping offers critical information in the context of genetic councelling

Molecular analysis of a case of thanatophoric dysplasia reveals two de novo FGFR3 missense mutations located in cis

Thanatophoric dysplasia [TD] is the most common form of lethal skeletal dysplasia. It is primarily an autosomal dominant disorder and is characterised by macrocephaly, a narrow thorax, short ribs, brachydactyly, and hypotonia. In addition to these core phenotypic features, TD type I involves micromelia with bowed femurs, while TD type II is characterised by micromelia with straight femurs and a moderate to severe clover-leaf deformity of the skull. Mutations in the FGFR3 gene are responsible for all cases of TD reported to date. The objective of the study here was to delineate further the mutational spectrum responsible for TD. Conventional polymerase chain reaction [PCR], allele-specific PCR, and sequence analysis were used to identify FGFR3 gene mutations in a fetus with a lethal skeletal dysplasia consistent with TD, which was detected during a routine antenatal ultrasound examination. In this report we describe the identification of two de novo missense mutations in cis in the FGFR3 gene [p.Asn540Lys and p.Val555Met] in a fetus displaying phenotypic features consistent with TD. This is the second description of a case of TD occurring as a result of double missense FGFR3 gene mutations, suggesting that the spectrum of mutations involved in the pathogenesis of TD may be broader than previously recognised