Distinctive phenotype in 9 patients with deletion of chromosome 1q24‐q25

Abstract

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170135865–172099327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.

1q25.2-q31.3 Deletion in a female with mental retardation, clinodactyly, minor facial anomalies but no growth retardation

“…The sizes and locations of two deletion cases reported by Burkardt (patient 9) [10] and Thienpont [7] are quite similar to ours. Burkardt [10] reported an 8-year-old boy with a 22.3 Mb 1q24.3-31.3 deletion who manifested growth retardation, psychomotor retardation, microcephaly, small ears, bilateral cleft lip and palate, micrognathia, loose nuchal skin, cryptorchidism, inguinal hernia, short limbs, small hands and feet, fifth finger clinodactyly and hypotonia.…”

“…The sizes and locations of two deletion cases reported by Burkardt (patient 9) [10] and Thienpont [7] are quite similar to ours. Burkardt [10] reported an 8-year-old boy with a 22.3 Mb 1q24.3-31.3 deletion who manifested growth retardation, psychomotor retardation, microcephaly, small ears, bilateral cleft lip and palate, micrognathia, loose nuchal skin, cryptorchidism, inguinal hernia, short limbs, small hands and feet, fifth finger clinodactyly and hypotonia. Thienpont [7] identified a 20.3 Mb 1q25.1-31.3 deletion in an 11-year-old boy who manifested growth retardation, psychomotor retardation, recurrent otitis media, narrow high-arched and triangular shaped palate, small hands and feet, fifth finger clinodactyly, abducted thumbs, persistent finger pads, 2–3 partial syndactyly of right foot, severe myopia and mild strabismus.…”

“…Two individuals of 1q25q32 deletion with LHX4 loss but no CENPL loss displayed significant growth retardation [7,11]. However, there were several discordant reports regarding LHX4 deletion and growth retardation [10,11]. Filges reported a female neonate with a maternally inherited 1q25.2q25.3 deletion affecting LHX4 but not CENPL had GH deficiency, but her mother was phenotypically normal [11].…”

A gene-centric study of common carotid artery remodelling

“…Chromosomal deletions at 1q24-25 result in a phenotype characterised by short stature and skeletal abnormalities [30] which suggests that this locus plays a role in extra-cellular matrix remodelling, but the precise underlying mechanism remains unclear. We have shown that the variants identified in this study are associated with altered expression levels of PIGC in aortic tissue.…”

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

“…Examples -just on the long arm of chromosome 1-include 1q43q44 microdeletions, 55,56 1q41q42 microdeletions, 57-59 and 1q24q25 microdeletions. 60,61 Further insight into microdeletion/microduplication syndromes comes by limiting comparisons of CNVs to just those with a phenotype of interest. For example, with 1q43q44 microdeletions, microcephaly, agenesis of the corpus callosum, and seizures appear to be caused by different SROs/genes.…”