Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation

The majority of deletions of the short arm of chromosome 5 are associated with cri du chat syndrome (CdCS) and patients show phenotypic and cytogenetic variability. To perform a genotype-phenotype correlation, 80 patients from the Italian CdCS Register were analysed. Molecular cytogenetic analysis showed that 62 patients (77.50%) had a 5p terminal deletion characterised by breakpoint intervals ranging from p13 (D5S763) to p15.2 (D5S18). Seven patients (8.75%) had a 5p interstitial deletion, four (5%) a de novo translocation, and three (3.75%) a familial translocation. Of the remaining four patients, three (3.75%) had de novo 5p anomalies involving two rearranged cell lines and one (1.25%) had a 5p deletion originating from a paternal inversion. The origin of the deleted chromosome 5 was paternal in 55 out of 61 patients (90.2%). Genotype-phenotype correlation in 62 patients with terminal deletions highlighted a progressive severity of clinical manifestation and psychomotor retardation related to the size of the deletion. The analysis of seven patients with interstitial deletions and one with a small terminal deletion confirmed the existence of two critical regions, one for dysmorphism and mental retardation in p15.2 and the other for the cat cry in p15.3. Results from one patient permitted the cat cry region to be distally narrowed from D5S13 to D5S731. Furthermore, this study lends support to the hypothesis of a separate region in p15.3 for the speech delay.


Keywords: cri du chat syndrome; 5p deletion; phenotype-genotype correlation; FISH     

Terminal 14q32.33 deletion: genotype-phenotype correlation

We report on a female infant presenting with psychomotor retardation and facial dysmorphism. Cytogenetic studies showed an abnormal chromosome 14 with ectopic NOR sequences at the extremity of the long arm with a terminal 14q32.33 deletion. Review of the eight cases with pure terminal 14q32.3 deletions described to date documented that our observation is the smallest terminal 14q deletion ever reported. Thus, genotype-phenotype correlation allows us to delimit the critical region for mental retardation, hypotonia, epi-telecanthus, short bulbous nose, long philtrum, thin upper lip, and small mouth observed in 14 qter deletions to the subtelomeric 1.6 Mb of chromosome 14.     

Subtelomeric deletion of chromosome 10p15.3: Clinical findings and molecular cytogenetic characterization

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study. ? 2012 Wiley Periodicals, Inc.     

Pure 6p22-pter trisomic patient: refined FISH characterization and genotype-phenotype correlation

First described in 1971, partial trisomy 6p is uncommon and generally secondary to a familial reciprocal translocation. The proximal breakpoint of the reported cases varies from p11 to p25. We here report on a patient with moderate mental retardation, craniofacial and pigmentary anomalies, proteinuria, and hyperglycemia who was found to have a mosaic karyotype 46,X,add(Y)(q12)/45,X. Fluorescence in situ hybridization (FISH) enabled us to identify that the additional material on Yqh derived from 6p and to define the rearrangement as der(Y)t(Y;6)(q12;p22). To the best of our knowledge, this is the first case of trisomy 6p22-pter without an associated deleted segment; the second breakpoint of the rearrangement is in Yqh. Precise mapping of the centromeric breakpoint of the trisomic 6p segment allowed a more convincing correlation between partial 6p trisomy and clinical phenotype to be addressed. In particular, the proteinuria often observed in 6p trisomic patients could be assigned to the 6p22-6pter region.     

Cytogenetic and molecular characterization of a three-generation family with chromosome 5p terminal deletion

Terminal or interstitial deletion on the short arm of chromosome 5 is associated with a genetic disorder, cri-du-chat syndrome (cat cry syndrome), which is characterized by a cat-like cry in infancy, facial dysmorphism, microcephaly, and mental retardation. There is a high degree of variation in clinical presentations of patients with cri-du-chat syndrome, which is usually associated with different sizes and locations of deletions in chromosome 5p. Most patients with a 5p deletion have de novo mutations; familial 5p deletion is rare in literature. Here, we report a three-generation family with a 5p terminal deletion. The terminal 5p deletion (5p15.2-pter) in this family was confirmed and characterized by karyotyping analysis, fluorescent in situ hybridization, array comparative genome hybridization, and quantitative polymerase chain reaction. Although the affected family members apparently share deletions of the same size, there are some variations in mental symptoms within this family. Two affected females manifest moderate mental retardation and psychotic symptoms such as delusion of persecution, auditory hallucination, self-talking, and self-laughing, which are rare in cri-du-chat syndrome. In contrast, the other three affected males express mild-to-moderate mental retardation but no psychotic symptoms. Our study suggests that other factors besides the size and location of 5p deletions may modify the mental presentations of patients with 5p deletions.     

Interstitial deletion of chromosome 2p15-16.1: report of two patients and critical review of current genotype-phenotype correlation

We report two individuals with developmental delay and dysmorphic features, in whom array-based comparative genomic hybridization (array CGH) led to the identification of a 2p15p16.1 de novo deletion. In the first patient (Patient 1) a familial deletion of 6q12, inherited from her father, was also detected. In the second patient (Patient 2) in addition to the 2p15p16.1 microdeletion a de novo deletion in Xq28 was detected. Both individuals shared dysmorphic features and developmental delay with the six reported patients with a 2p15p16.1 microdeletion described in medical literature. Conclusion: in the first patient a 642 kb 2p16.1 deletion (from 60.604 to 61.246 Mb), and a 930 kb 6q12 familial deletion, was detected and in the second a 2.5 Mb 2p15p16.1 deletion (from 60.258 to 62.763 Mb), with a Xq28 deletion, was discovered. The common dysmorphic features and neurodevelopmental delay found in these patients are in agreement with the clinical phenotype of a microdeletion syndrome involving 2p15p16.1. Our data confirm the hypothesis suggesting that 2p15p16.1 deletion is a contiguous gene syndrome.     

Refined genotype-phenotype correlations in cases of chromosome 6p deletion syndromes

Clinical reports of cases with deletions in chromosome 6p are relatively rare. We present a detailed study by fluorescent in situ hybridisation (FISH) of six new cases with distinct but overlapping 6p deletions involving the 6p24-pter chromosomal segment. Chromosomal breakpoints in individual cases were investigated using a large panel of probes previously mapped and characterised in our laboratory to cover the distal region of 6p. These cases have allowed refinement of genotype-phenotype correlations and strongly suggest a gene involved in regulating the development of hearing is localised within 6p25. There is also evidence for one or more loci involved in heart, skeletal and craniofacial development in the 6p24-p25 region. Furthermore, the Dandy-Walker malformation is associated with deletion of 6p24-pter.     

Clinical and molecular analyses of deletion 3p25-pter syndrome

Hemizygous deletion of 3p25-pter is associated with a phenotype of profound growth failure, microcephaly, characteristic facial changes, and mental retardation. Since the severity may be quite variable, we have studied 3 cases of del 3p25-pter to define the clinical manifestations and the critical chromosome region for phenotypic expression. The patient we now report died at age 6 months and provided an opportunity for a detailed necropsy analysis for only the second time in a del(3p) patient. He had marked hypoplasia of all organs, hypomyelination of white matter, and multiple renal cortical microcysts. Ordered genomic markers from the distal regions of chromosome 3p aided in determining the parent of origin of each deletion and in defining the boundaries of the deleted chromosomal segments. The deleted markers distal to the RAF1 oncogene in 2 of the 3 patients were consistently hemizygous. One patient had an interstitial deletion based on evidence of diploid inheritance of one of the most distal loci (D3S17). Available genetic linkage maps suggest that the deletion spans at least 19 centimorgans (cM). © 1993 Wiley-Liss, Inc.     

Small familial supernumerary ring chromosome 2: FISH characterization and genotype-phenotype correlation

A child and his mother were found to be mosaic for a small supernumerary marker chromosome (SMC) that was identified and characterized by means of fluorescent in situ hybridization. The marker chromosome was derived from the pericentromeric region of chromosome 2; the involvement of proximal 2q was determined by YAC probes. The proband was referred because of psychotic illness and mild mental retardation, whereas his mother presented only minor dysmorphisms. There are only a few published reports concerning SMC(2) or proximal 2q trisomy. We reviewed the previously reported cases in an attempt to establish genotype-phenotype correlations, which are particularly important when SMCs are identified in prenatal diagnosis.     

Clinical and molecular characterization of a patient with a 2q31.2-32.3 deletion identified by array-CGH

We report on a patient with a de novo interstitial deletion of the long arm of chromosome 2 involving bands 2q31.2-2q32.3. The patient shows severe mental retardation, absence of speech, sleep disturbances, behavioral problems, and some dysmorphic features. In particular, he presents with macrocephaly, high forehead, thick and coarse hair, thick eyebrows, synophrys, increased inner and outer canthal distance, bifid nasal tip, high palate, micrognathia, dysmorphic right ear, and long and tapering fingers. Array-CGH analysis allowed us to identify and characterize a 2q interstitial deletion of about 13 Mb, involving the segment between cytogenetic bands 2q31.2 and 2q32.3. The deletion was confirmed by quantitative PCR. We compare the phenotype of our patient with those already reported in literature. In particular, we discuss the similarities shared with two recently reported patients, studied by array-CGH, who show an overlapping deletion. The common clinical features are: long face, high forehead, abnormal teeth and ears, midface hypoplasia, high palate, micrognathia, transparent and thin skin, high frequency of inguinal hernia, severe development impairment, and behavioral problems. Some genes located in the deleted region may be good candidates for the neurological phenotype such as ZNF533 and MYO1B, which are both involved in neuronal function. Furthermore, the GLS gene could be a good candidate in generating the behavioral phenotype in the patient. In fact, it encodes for the major enzyme yielding glutamate from glutamine and it can be implicated in behavioral disturbances in which glutamate acts as a neurotransmitter.     

Clinical and molecular characterization of two patients with a 6.75 Mb overlapping deletion in 8p12p21 with two candidate loci for congenital heart defects

Clinical and molecular characteristics of two patients with a 6.75 Mb overlapping interstitial deletion in the 8p12p21 region are described and compared with previously reported cases with an overlapping deletion. The most common characteristics of interstitial deletions of proximal 8p are developmental delay, postnatal microcephaly and growth retardation. Other frequently reported findings are hypogonadism associated with haploinsufficiency of GNRH1 and ocular problems. Congenital heart anomalies are also common and might at least to some extent be due to haploinsufficiency of NKX2-6 or NRG1. The aforementioned clinical characteristics should be considered in the care of patients with a proximal interstitial 8p12p21 deletion.     

Follow-up of adult males with chromosome 18p deletion

The 18p- syndrome has been known for over 40 years, the first report being by de Grouchy et al. [Comptes Rendus Hebdomadaires Séances l'Acad Sci 256 (1963) 1028]. Mental retardation of varying severity is the most constant feature. Over 100 cases have been reported. The eldest patients have been 50 years [Hum Genet 63 (1983) 139; Clin Genet 2 (1971) 338]. Follow-up of two adult patients, then 22 and 42 years [Ann Génét 29 (1986) 107], now 42 and 62 years of age, is reported. Further case reports are required in order to better define the evolution of adult patients with the 18p- syndrome.     

Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis

Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.     

Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study

Oral–facial–digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype–genotype correlation was performed using χ² test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype–genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non‐random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype–genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.