Mother and Daughter with Short Stature, Microcephaly, Mild Dysmorphic Features, and Learning Disabilities Due to Ververi-Brady Syndrome Associated with a New Variant of the Gene

Background

The first cases of intellectual disability combined with dysmorphic features and de novo heterozygous loss-of-function variants in the Glutamine-rich protein 1 (QRICH1) gene were reported in 2018 by Ververi et al, describing 3 unrelated children [1]. The first 3 patients were diagnosed by whole exome sequencing, in which array-based comparative genome hybridization was used to perform high-resolution analysis for copy number abnormalities [1]. All of them shared similar features and syndromic phenotype, as well as different loss-of-function mutations; therefore, the syndrome was named for its discoverers, Ververi-Brady (VEBRAS) [1]. In the next few years, a few more case studies appeared, broadening the clinical spectrum of this disorder [2]. According to recent studies, the QRICH1 gene is likely to be involved in apoptosis and inflammation, as well as the hypertrophic differentiation required for normal longitudinal bone growth [3]. You et al showed the role of QRICH1 in maintaining tissue homeostasis during pathological conditions such as inflammatory or metabolic disorders [4]. Recently, Kumble et al published a study of 38 cases, summarizing all previously known clinical and genetic information about pathogenic QRICH1 variants [5]. Overall, 35 different pathological variants have been described until now, with most predicted as protein-truncating variants [5]. However only 4 individuals with inherited pathogenic variants have been described lately, showing paternal inheritance in 3 cases and 1 of maternal inheritance [5]. This report is of a mother and daughter with VEBRAS, associated with a new variant of the QRICH1 gene, NM_017730.3: c.337C>T; p.(Gln113*).

Case Reports

CASE 1:

The 17-year-old female patient was the first and only child of healthy non-consanguineous parents (Figure 1). Her mother gave no history of previous illnesses or substance misuse during pregnancy; however, she had a history of multiple miscarriages. The mother did not reported any history of preeclampsia, gestational diabetes, or other complications during pregnancy with the proband, who was born prematurely at gestational week 27 by caesarean section. Apgar scores were 2, 3, and 5 at minute 1, minute 5, and after resuscitation, respectively. Her birthweight was 1.139 kg, height 36 cm, and head circumference 25.5 cm. She developed early respiratory distress and was admitted to the Intensive Care Unit for mechanical lung ventilation. On day 14 after birth, hemangiomatosis appeared. She had proportionally short stature, multiple hemangiomas on the face, neck, and extremities, as well as a small tongue and narrow and high-arched palates. Her further motor and cognitive development were slightly delayed: she started crawling at the age of 6 months, at 12 months of age she was able to stand but only with support, and she started walking at 16 to 18 months of age, approximately. She had had mild right-sided paresis, suspectedly caused by perinatal hypoxic ischemic brain injury. At the age of 13 years, she was referred to a neurologist for the first time, with focal motor seizures in the hands, which progressed to bilateral tonic-clonic seizures. She was started on treatment with oxcarbazepine and levetiracetam; unfortunately, the initial doses were unknown (was currently on levetiracetam 1000 mg twice daily); however her electroencephalogram results worsened with time, showing epileptic encephalopathy and dysfunction with epileptiform elements. Magnetic resonance imaging (MRI) was performed, and she was referred to a geneticist at the age of 17 years to exclude inherited leucodystrophies.

On the first examination with the geneticist, her height was 155 cm, weight was 36 kg, and body mass index was 14.98 kg/m2. She had mild scoliosis, broad forehead, prominent long nose, hypertelorism, smooth philtrum, thin upper lip, hirsutism, and mild gaze deviation. Also, occipital balding was observed (Figure 2). On neurologic examination, she had mild spastic paresis in her right leg, with initial contractures in the Achilles tendon. She attended elementary school, but had difficulties with concentration and focusing on tasks. During examination, she avoided eye contact but was otherwise cheerful and communicative. Her mother reported no signs of aggressive behavior, although she noted that her daughter could appear easily irritated. She underwent repeated laser surgeries for her hemangiomatosis and did not have any signs of them felt.

CASE 2:

The patient was a 49-year-old woman with no previous significant medical history other than multiple miscarriages. She was also the only child of healthy, unrelated parents and cannot recall any additional information about her birth. However, she remembered that her mother was short-statured, at 155 cm. Similar to her daughter in case 1, this patient had short stature, broad forehead, prominent nose, thin upper lip, and occipital balding (Figure 3). She could make eye contact during conversation; however, she was easily distracted and inconsistent answering questions. Considering her history of miscarriages, she had visited a gynecologist, but no objective reason for miscarriage was found, according to her.

All things considered, further genetic testing was recommended and offered to both mother and daughter. Also, MRI was performed in both patients, revealing periventricular, symmetric transverse relaxation time (T2) and fluid-attenuated inversion recovery (FLAIR) hyperintense white matter lesions in both hemispheres in the daughter (Figure 4). In the mother, the investigation did not reveal any specific brain matter lesions (Figure 5).

Considering the radiologic findings and clinical presentation, inherited leukodystrophy was suspected and a Blueprint Genetics Leukodystrophy and Leukoencephalopathy panel was performed; however, this analysis did not detect any known disease-causing mutations or novel variants that were considered deleterious. All things considered, we proceeded with whole exome sequencing, which identified a novel heterozygous variant in the QRICH1 gene, classified as pathogenic according to the American College of Medical Genetics 2015 criteria (the variant results in nonsense change and is predicted to undergo nonsense-mediated decay, and loss-of-function is a well-known disease mechanism for the QRICH1 gene [PVS1]; the variant is not present in gnomAD v2.1.1. or v3.1.1. [PM2]; the variant segregates with the phenotype in the family [PP1]). The variant was segregated in the mother using Sanger sequencing (Figure 6).

Discussion

VEBRAS remains a rare entity with a large spectrum of pathogenic QRICH1 variants and a phenotypic appearance that continues to expand. Our cases highlight the importance of a clinical geneticist when it comes to diagnosing a patient with multiple organ system involvement and dysmorphic features.

Intellectual disability by itself may not be the reason to seek medical attention and perform additional investigations, as we can see in our patients. Unlike most of the previously reported cases, our patients were 17 and 49 years old at first evaluation with a geneticist, despite the premature birth and health problems during infancy in the patient in case 1. The summary of preceding cases shows that most were seen during the first decade of a patient’s life. Our case is similar to another case, which was also of maternal inheritance, and in our case, we can speculate about the mother’s cognitive impairment as a potential reason for lacking awareness of the child’s condition [5].

The first patients with described de novo variants in the QRICH1 gene had a similar phenotype, with intellectual disability, motor and/or language delay, and facial dysmorphism, like our patients [1]. In the next few years, new cases with different pathogenic variants in the QRICH1 gene were discovered and the clinical spectrum has noticeably broadened [2,3,6,7]. In a case series by Lui et al, 2 children with diminished stature and irregular proximal phalangeal growth plates were described, with the authors thereby proposing the theory that heterozygous mutation in QRICH1 induces subtle chondrodysplasia [6]. A year later, a group of researchers lead by Föhrenbach presented a case study of 4 more patients and reported more clinical features, such as scoliosis and brain matter abnormalities [7]. Recently, a large study by Kumble et al was published, adding clinical and genetical information about another 27 patients with different mutations in the same gene [5]. According to their study, the most common clinical feature is facial dysmorphism, presenting in 92% of all patients; motor and language delay as well as intellectual disability are also present in two-thirds of described patients; however short stature and low weight, previously supposed to be 2 of the main features, are present in only 32% and 29%, respectively [5]. Our patient in case 1 presented with many of the already reported abnormalities, such as motor and intellectual delay, scoliosis, facial dysmorphism, short stature, seizures, and structural brain abnormalities. Nevertheless, during the initial investigation, there were no signs of cardiac or renal involvement, as described in a few other patients [5]. On the other hand, the patient in case 2 had only intellectual disability and mild facial dysmorphism and did not consider herself as affected. Therefore, it is important to pay attention and uncover genetic abnormalities leading to developmental and intellectual delays, as it could be only part of the clinical spectrum in cases of QRICH1 pathogenic variants.

The overall function of the QRICH1 gene remains largely unknown, and recent studies support its role in integrating the stress response through maintaining proteostasis in the endoplasmic reticulum [4]. Considering the gene expression in almost all investigated cases, a tissue-wide spectrum of clinical variability in pathologic variants can be expected [4]. Taking into account all available information about pathogenic QRICH1 variants, it seems that the disorder can affect not only the musculoskeletal and nervous system but also internal organs such as the heart and kidneys, which is one of the reasons for Kumble et al to suggest using the term “QRICH1-associated neurodevelopmental disorder” [5].

The reported proband and her mother have some additional, previously undescribed features, including occipital balding, infantile hemangiomatosis, and probable impaired fecundity. Considering the novelty of QRICH1-associated neurodevelopmental disorder, it seems to be crucial to thoroughly evaluate and investigate every individual with pathogenic QRICH1 variants in order to provide better follow-up care and counseling for affected individuals and families.

Another noteworthy aspect in this case was the gene panel of choice when we suspected an inherited disorder. As can be seen, initial presentation and radiologic features led us in the wrong direction, resulting in a diagnostic delay of at least a few months. It was not lifesaving or an essential amount of time in this case; nevertheless, any clinician should be watchful and avoid any postponements in diagnosis if possible. Today, genetic testing is becoming progressively available; however, it does not always give answers when it comes to rare disorders. Therefore, we suggest proceeding with whole exome sequencing prior to gene panel testing for unknown and potentially rare disorders with multiple organ system involvement.

Conclusions

This case highlights multiple diagnostic challenges of rare diseases with phenotypic variability. Considering the small number of previously described patients with a QRICH1-associated neurodevelopmental disorder, reporting every single newly discovered case could be beneficial for improvement in further diagnostic algorithms and treatment strategies. This report has also highlighted the importance of clinical genetics in the identification of familial genetic disorders with complex phenotypes. Many questions still need to be answered, especially when it comes to a potential screening scheme. For example, is renal, cardiac, or genitourinary involvement specific for VEBRAS or it is just a coincidence? Further delineation of genotype and phenotype is required to establish a definite correlation.