RESUMO
Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated â¼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).
Assuntos
Anormalidades Múltiplas/genética , Perda Auditiva/genética , Deficiência Intelectual/genética , Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Motivos de Aminoácidos , Bases de Dados Genéticas , Expressão Gênica , Haploinsuficiência , Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/patologia , Microcefalia/diagnóstico , Microcefalia/patologia , Modelos Moleculares , Dados de Sequência Molecular , Penetrância , Fenótipo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Splicing de RNA , Spliceossomos/genéticaRESUMO
The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 8/genética , Deficiências do Desenvolvimento/genética , Duplicação Gênica/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Fator de Transcrição GATA4/genética , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Masculino , SíndromeRESUMO
We report a male child born with complete absence of his external ear, hemifacial microsomia of the right side, high arched palate, a down-turned upper lip and slightly up-slanting palpebral fissures. The features were suggestive of facio-auriculo-vertebral spectrum. Investigations showed a tandem duplication of the short arm of one chromosome 10 with apparent breakpoints at p14 and p15. This case extends the list of chromosomal abnormalities associated with the facio-auriculo-vertebral phenotype and also adds useful clinical information to possible trisomy 10p phenotypes.
