Mental retardation-40 (MRD40) is a rare autosomal dominant neurodevelopmental disorder with a poor prognosis that is caused by a heterozygous mutation in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). It was previously considered a non-syndromic disease due to the lack of specific external features. Only limited international reports describing CHAMP1 mutations are currently available. The present case study was the first to report on a Chinese patient with MRD40. The patient presented with severe global development delay with significant craniofacial dysmorphia. Using trio whole-exome sequencing, a novel
Autosomal dominant intellectual disability (ID), previously known as mental retardation, is a series of Mendelian neurodevelopmental disorders that result in ID (
The Deciphering Developmental Disorders (DDD) Study (
The present study reported on a Chinese pediatric patient diagnosed with MRD40 due to a CHAMP1 truncating mutation identified by whole-exome sequencing (WES). A practical online workflow of a comprehensive trio WES analysis was used in the present study, as recommended by the DDD study (
The patient was a four-month-old male admitted to the Third Affiliated Hospital of Zhengzhou University (Zhengzhou, China) due to delayed development. His anomalies in appearance included a tented upper lip, a high-arched palate and open-mouth appearance (
The patient was the first-born child and delivered by full-term, natural labor, and a family history of diseases in the neurological system was not present.
Laboratory tests indicated slightly elevated urine oxalic acid, succinic acid and glyceric acid levels; brain MRI revealed symmetric enlargement in the bilateral lateral ventricle (
The patient was provided with proper rehabilitation training, but at the age of 1 year and 3 months, the patient still had difficulties acquiring language skills and was not able to stand up by himself. In addition, the patient was monitored continuously. The patient displayed a severe developmental delay at the age of 9 months with microcephaly (
EDTA-treated peripheral blood samples for the trio-WES analysis were collected from the patient and the patient's parents to detect germline variation. Genomic DNA was extracted from blood samples using the Blood Genome Column Medium Extraction Kit (Kangweishiji). Protein-coding exome enrichment was performed using xGen Exome Research Panel v1.0 (Integrated DNA Technologies), which consists of 429,826 individually synthesized and quality-controlled probes that target a 39-Mb protein-coding region (19,396 genes) of the human genome and cover 51 Mb of end-to-end tiled probe space. High-throughput sequencing was performed using an Illumina NovaSeq 6000 series sequencer (PE150; Illumina, Inc.). The sequencing process was performed by the Beijing Chigene Translational Medicine Research Center Co., Ltd. Variants were called and files in binary alignment map format were screened for insertions/deletions and recalibrated using The Genome Analysis Toolkit (
After sequencing, the data were processed using the Illumina DNA sequencing data analysis pipeline (
For the literature review, the PubMed (
A novel
According to the results, the patient was diagnosed with MRD40. Of note, the pediatric patient of the present study was the first Chinese case to be reported to have a CHAMP1 mutation.
At the time the present study was submitted, 18 cases of MRD40 had been reported, including the present case, and this patient was the first known affected individual in China. As a result, GDD/ID with speech delay, motor developmental delay and facial anomalies were observed in all patients, as well as hypotonia (17/18), abnormal muscular tone (16/18), vision damage (15/18), abnormal behaviors (14/18) and reproductive issues (13/18) were quite common in patients with MRD40, while seizures (4/18), abnormal hearing (3/18) and spasticity (4/18) were less prevalent phenotypes. The clinical features of the above-mentioned patients are listed in
NS-ID refers to a rare, hereditary, neurological disease characterized by early-onset cognitive impairment as the sole disability (
The human CHAMP1 protein is an 812-amino-acid zinc-finger protein that is located on chromosome 13q34 and is expressed in the fetal brain during development and in all adult tissues (
Thus, based on these findings, all of the truncating mutations (
WES is a powerful tool for the diagnosis of neurodevelopmental disorders; however, the analysis of massive amounts of data has been a major challenge (
Not applicable.
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request. The sequencing data have been uploaded to a curated repository (
YD made substantial contributions to conception and design, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. XS participated in drafting the manuscript acquired, analyzing and interpreting the data. KD, TJ and JW participated in acquisition and interpretation of data, revising the manuscript critically for important intellectual content. RX, LW and RH participated in analyzing and interpreting the data. YD and KD confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Ethical approval for the present study was obtained from the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Zhengzhou, China; no. 2019116).
Informed consent was obtained from the parents of the patient included in the study for genetic testing and publication of data and images.
The authors declare that they have no competing interests.
Images displaying dysmorphic features at different ages. Features included a tented upper lip, open-mouth appearance, low-set ears, sparse hair in general and microcephaly at the age of (A and B) 4 months and (C) 9 months.
Brain MRI at the age of 4 months: Bilateral lateral ventricle fullness is presented in (A) T1-weighted, (B) T2-weighted and (C) T2 fluid-attenuated inversion recovery images. (D) Sagittal imaging revealed the features of the lip and high-arched palate.
Mutation in the chromosome alignment maintaining phosphoprotein 1 gene: A frameshift mutation (c.530delCinsTTT, p.Ser177Phefs*2) was detected in the proband using Sanger sequencing, while the proband's parents did not carry the mutation. Sequenced data were aligned to the reference human genome (hg19;
Summary of patients with mutations in chromosome alignment maintaining phosphoprotein 1.
Case no. |
Author (year) | Nationality of the case | Age | Sex | GDD/ID | Feeding difficulty | Seizures | Delay in motor development | Speech delay | Abnormal behavior | Muscular hypotonia | Spasticity | Abnormal vision | Abnormal hearing | Dysmorphic features | (Refs.) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | Okamoto (2017) | Japanese | 6 y | M | + | + | + | + | + | + | - | + | + | - | + | ( |
2 | Isidor (2016) #1 | French | NA | M | + | + | - | + | + | - | + | - | + | - | + | ( |
3 | Isidor (2016) #2 | UK | NA | M | + | - | - | + | + | - | + | - | + | - | - | ( |
4 | Isidor (2016) #3 | USA | NA | F | + | NA | + | + | + | + | + | - | + | - | + | ( |
5 | Isidor (2016) #4 | USA | NA | M | + | - | + | + | + | + | - | + | - | + | ( |
|
6 | Isidor (2016) #5 | UK | NA | F | + | + | - | + | + | + | + | - | NA | - | + | ( |
7 | Isidor (2016) #6 | UK | NA | F | + | NA | NA | + | + | - | + | - | + | - | + | ( |
8 | Hempel (2015) #1 | NA | 4 y | M | + | + | - | + | + | + | + | - | + | - | + | ( |
9 | Hempel (2015) #2 | Dutch | 3 y | M | + | + | + | + | + | + | + | - | + | - | + | ( |
10 | Hempel (2015) #3 | Dutch | 18 y | M | + | + | - | + | + | + | + | - | + | - | + | ( |
11 | Hempel (2015) #4 | Dutch | 3 y | F | + | + | - | + | + | + | + | - | + | - | + | ( |
12 | Hempel (2015) #5 | German | 9 y | F | + | - | - | + | + | + | + | - | + | - | + | ( |
13 | Tanaka (2016) #1 | NA | 23 y | F | + | + | - | + | + | + | + | + | - | + | + | ( |
14 | Tanaka (2016) #2 | NA | 7 y | F | + | + | + | + | + | + | - | + | + | - | + | ( |
15 | Tanaka (2016) #3 | NA | 4 y | F | + | + | - | + | + | + | + | + | + | + | + | ( |
16 | Tanaka (2016) #4 | NA | 12 y | F | + | + | + | + | + | + | + | - | + | - | + | ( |
17 | Tanaka (2016) #5 | NA | 6 y | F | + | + | - | + | + | + | + | - | + | + | + | ( |
18 | Dong (2020) | Chinese | 4 m | M | + | - | - | + | + | - | + | - | - | - | + | Current |
aCase number is the same with that in
Mutations in CHAMP1 and brain MRI features of patients with
Case no. | DNA change | Protein change | Mutation types | Brain MRI features |
---|---|---|---|---|
1 | c.2068_2069delGA | p.Glu690Serfs*5 | Frameshift | Cavum septum pellucidum, cavum vergae, cerebral atrophy, and decreased white matter volume |
2 | c.1880C>G | p.Ser627* | Nonsense | Normal or unremarkable findings |
3 | c.1002G>A | p.Trp334* | Nonsense | Normal or unremarkable findings |
4 | c.1876_1877delAG | p.Ser626Leufs*4 | Frameshift | Normal or unremarkable findings |
5 | c.1043G>A | p.Trp348* | Nonsense | Normal or unremarkable findings |
6 | c.958_959delCC | p.Pro320* | Frameshift | Normal or unremarkable findings |
7 | c.1489C>T | p.Arg497* | Nonsense | Normal or unremarkable findings |
8 | c.1866_1867delCA | p.Asp622Glufs*8 | Frameshift | Mild brain atrophy and cerebellar cortical dysplasia |
9 | c.1768C>T | p.Gln590* | Nonsense | Slightly delayed myelination |
10 | c.1192C>T | p.Arg398* | Nonsense | Normal |
11 | c.635delC | p.Pro212Leufs*7 | Frameshift | Normal |
12 | c.1192C>T | p.Arg398* | Nonsense | Normal |
13 | c.1044delG | p.Trp348* | Frameshift | Hypoplastic corpus callosum |
14 | c.542_543delCT | p.Ser181CysfsX5 | Frameshift | NA |
15 | c.1945C>T | p.Gln649* | Nonsense | Normal |
16 | c.1969C>T | p.Gln657* | Nonsense | Slightly decreased white matter volume, possible hypopituitarism |
17 | c.2029G>T | p.Glu677* | Nonsense | Mild cerebellar atrophy with mild inferior vermian hypogenesis |
18 | c.530delCinsTTT | p.Ser177Phefs*2 | Frameshift | Bilateral lateral ventricle fullness |
CHAMP1, chromosome alignment maintaining phosphoprotein 1; NA, not available.