A case of neonatal Cornelia de Lange syndrome caused by a novel variant of SMC1A gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a neonate with suggestive features of Cornelia de Lange Syndrome (CdLS).@*METHODS@#Chromosome karyotyping, copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were carried out for the child. Meanwhile, peripheral venous blood samples were taken from his parents for verifying the suspected pathogenic variants detected in the child.@*RESULTS@#The child has exhibited developmental delay, microcephaly, ptosis, micrognathia, and low ear setting, and was suspected as CdLS. No abnormality was found by karyotyping and CNV-seq analysis. WES has detected 5 heterogeneous variants and 1 hemizygous variant on the X chromosome. Combining the genetic pattern and result of family verification, a hemizygous C.3500T>C (p.ile1167thr) of the SMC1A gene was predicted to underlay the clinical manifestations of the patient. This variant was not recorded in the dbSNP and gnomAD database. PolyPhen2, Provean, SIFT all predicted the variant to be harmful, and PhastCons conservative prediction is was a conservative mutation. ACMG variant classification standard evidence supports are PM2, PP2, and PP3.@*CONCLUSION@#The novel c.3500T>C (p.Ile1167Thr) missense mutation of the SMC1A gene probably underlay the genetic etiology of CdLS in this child. Above results has enriched the mutation spectrum of CdLS type II, and facilitated clinical counseling for this family.

Diagnostico prenatal en Sindrome de Cornelia de Lange a propósito de 2 casos / Prenatal diagnosis in Cornelia de Lange syndrome in 2 cases

RESUMEN El Síndrome de Cornelia de Lange (SCdL) es un trastorno hereditario del desarrollo con transmisión dominante, aunque la mayoría de los casos son esporádicos. La prevalencia es variable oscilando entre 1/10.000-1/100.000 nacimientos. Se caracteriza por un fenotipo facial distintivo, anomalías en las extremidades superiores y retraso del crecimiento y psicomotor. El diagnóstico prenatal de este síndrome está limitado a la detección de anomalías mayores, ya que los rasgos fenotípicos distintivos del mismo no son fácilmente detectables. Suele cursar con aumento de la translucencia nucal, higroma quístico y valores de PAPP-A bajos en el primer trimestre de la gestación; retraso del crecimiento intrauterino, retromicrognatia, anomalías con grado variable de severidad de las extremidades superiores y otras anomalías cardiovasculares, gastrointestinales o genitourinarias que condicionan el pronóstico fetal. Se presentan los hallazgos ecográficos de dos casos con sospecha de afectación por el SCdL, y la correlación entre los mismos y los hallazgos en la necropsia. Al establecer la sospecha diagnóstica de forma retrospectiva, en los casos presentados no fue posible estudiar la presencia de mutaciones genéticas asociadas con el SCdL. A pesar de los avances en el diagnóstico genético de este síndrome, la base genética del mismo es todavía desconocida en alrededor del 30% de los pacientes, lo que sugiere la contribución de otros genes y/o factores ambientales en su etiología.

ABSTRACT Cornelia de Lange Syndrome (CdLS) is an hereditary developmental disorder with dominant condition, although most cases are sporadic. The prevalence is variable ranging from 1/10,000 to 1/100,000 live births. It is characterized by a distinct facial phenotype, upper limb abnormalities, growth retardation and severe mental retardation. Prenatal diagnosis of this syndrome is limited to detecting major abnormalities, since characteristic facial features aren't easily detectable. Is usually associated with increased nuchal translucency, cystic hygroma and low PAPP- A levels in first trimester of pregnancy; intrauterine growth retardation, retromicrognathia, anomalies with varying degrees of severity of upper limbs and other cardiovascular, gastrointestinal or genitourinary abnormalities that affect fetal prognosis. The sonographic findings of two cases with suspected involvement by CdLS, and the correlation between them and necropsy findings are presented. Since the suspected diagnosis was established retrospectively in the presented cases, it wasn't possible to study the association with CdLS gene mutations. Despite advances in genetic diagnosis of this syndrome, the genetic basis of it still unknown in about 30% of patients, suggesting the contribution of other genes and/or environmental factors in its etiology.

Nucleotide sequence analysis of NIPBL gene in Indian Cornelia de Lange syndrome cases.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder in children. The disorder is caused mainly due to mutations in Nipped-B-like protein. The molecular data for CdLS is available from developed countries, but not available in developing countries like India. In the present study, the hotspot region of NIPBL gene was screened by Polymerase Chain Reaction which includes exon 2, 22, 42, and a biggest exon 10, in six CdLS patients and ten controls. MATERIALS AND METHODS: The method adopted in present study was amplification of the target exon by using polymerase chain reaction, qualitative confirmation of amplicons by Agarose Gel Electrophoresis and use of amplicons for Conformation Sensitive Gel Electrophoresis to find heteroduplex formation followed by sequencing. RESULTS: We report two polymorphisms in the studied region of gene NIPBL. The polymorphisms are in the region of intron 1 and in exon 10. The polymorphism C/A is present in intron 1 region and polymorphism T/G in exon 10. CONCLUSION: The intronic region polymorphism may have a role in intron splicing whereas the polymorphism in exon 10 results in amino acid change (Val to Gly). These polymorphisms are disease associated as these are found in CdLS patients only and not in controls.

Síndrome de Cornelia de Lange: relato de dois casos com variabilidade clínica / Cornelia de Lange syndrome: report of two cases with clinical variability

O objetivo deste trabalho é relatar dois casos de pacientes com síndrome de Cornelia de Lange, comparando seus quadros clínicos com os achados da literatura e ressaltando a variabilidade fenotípica existente que, eventualmente, pode dificultar o diagnóstico. São apresentados os relatos de dois pacientes com a síndrome. No primeiro caso a criança tem um quadro típico clássico, enquanto a segunda apresenta uma forma moderada da síndrome. O diagnóstico da síndrome de Cornelia de Lange é eminentemente clínico. A despeito de três genes terem sido identificados como possíveis causadores dessa síndrome, exames moleculares para confirmação diagnóstica não estão disponíveis na prática médica cotidiana e, mesmo quando factíveis, podem não confirmar uma suspeita clínica. Neste artigo se discutem as distintas apresentações fenotípicas da síndrome e os critérios clínicos mínimos necessários para confirmação diagnóstica.

Síndrome de Cornelia de Lange / Cornelia de Lange syndrome

El Síndrome de Cornelia de Lange (SCL) es un cuadro malformativo poco frecuente, caracterizado por la presencia de retraso del crecimiento, microcefalia, retardo mental, hirsutismo, dismorfias faciales características y defectos en las extremidades. Se estima una incidencia de 1:10.000 a 1:40.000 recién nacidos vivos, siendo la mayoría casos esporádicos, aunque algunos pocos se han publicado con una herencia de tipo autosómico dominante. Existen dos genes responsables del SCL: el NIPBL, que ha sido recientemente identificado y mapeado en 5p13.1, y el SMC1L1 en Xp11.22 –p11.21, descubierto también recientemente en varios sujetos afectados y con herencia ligada al X. Mutaciones en el gen NIPBL se han encontrado en el 40 por ciento a 50 por ciento de los pacientes afectados clínicamente por el cuadro. En esta revisión presentamos el caso de una paciente de seis años de edad, con diagnóstico clínico de SCL, con el objetivo de dar a conocer esta patología malformativa, que forma parte del diagnóstico diferencial de los cuadros clínicos con retardo mental.

Cornelia de Lange Syndrome (CdLS) is a rare malformative disease. It is characterized by the presence of growth retardation, microcephaly, mental retardation, hirsutism, facial alterations and defects in the extremities. Incidence is 1:10,000 to 1:40,000 in newborns. Most cases are sporadic, although some cases have been published with autosomal dominant inheritance. Two recently identified genes are responsible for CdLS: NIPBL, located on 5p13.1, and SMC1L1, located on Xp11.22 –p11.21 and present in several affected subjects, and with X-linked inheritance. Mutations of NIPBL genes are described in 40 to 50 percent of patients. We present the case of a six year old patient, with clinical diagnosis of CdLS, with the purpose of presenting this malformative disease, which is part of the differential diagnosis of clinical manifestations associated to mental retardation.