Human microcephaly

Microcephaly is defined as a reduction in head circumference and this clinical finding infers that an individual has a significant diminution in brain volume. Microcephaly can be usefully divided into primary microcephaly, in which the brain fails to grow to the correct size during pregnancy, and secondary microcephaly, in which the brain is the expected size at birth but subsequently fails to grow normally. Current work suggests that primary microcephaly is caused by a decrease in the number of neurones generated during neurogenesis, but that in secondary microcephaly it is the number of dendritic processes and synaptic connections that is reduced. Important insights into human neurogenesis are being revealed by the study of rare genetic diseases that involve primary microcephaly, illustrated by the identification of the Microcephalin, abnormal spindle in microcephaly and ataxia-telangiectasia and Rad3-related genes. Furthermore, these findings facilitate the search for the evolutionary changes that have lead to the human brain being so much larger than that of any other primates.     

Genetic analysis of microcephaly]

A clinical genetic examination of 22 cases of hereditary microcephaly in 11 families was carried out. Parent consanguinity (first and second cousins) was ascertained in 7 families. Genetic analysis of the experimental material performed by Weinberg's method showed significantly recessive course of the genuine microcephaly inheritance. High frequency of low degree mental retardation (30%) among probable recessive genes carriers of microcephaly (of the parents and their siblings) was ascertained and that confirmed the possibility of gene heterozygous state manifestation. The gene frequency fluctuated from 0,0042 to 0,024. About 3500 people might show low forms of mental retardation in connection with probable non-penetration (about 30%) of the microcephaly genes being in heterozygols state.     

Angelman syndrome protein UBE3A interacts with primary microcephaly protein ASPM, localizes to centrosomes and regulates chromosome segregation

Many proteins associated with the phenotype microcephaly have been localized to the centrosome or linked to it functionally. All the seven autosomal recessive primary microcephaly (MCPH) proteins localize at the centrosome. Microcephalic osteodysplastic primordial dwarfism type II protein PCNT and Seckel syndrome (also characterized by severe microcephaly) protein ATR are also centrosomal proteins. All of the above findings show the importance of centrosomal proteins as the key players in neurogenesis and brain development. However, the exact mechanism as to how the loss-of-function of these proteins leads to microcephaly remains to be elucidated. To gain insight into the function of the most commonly mutated MCPH gene ASPM, we used the yeast two-hybrid technique to screen a human fetal brain cDNA library with an ASPM bait. The analysis identified Angelman syndrome gene product UBE3A as an ASPM interactor. Like ASPM, UBE3A also localizes to the centrosome. The identification of UBE3A as an ASPM interactor is not surprising as more than 80% of Angelman syndrome patients have microcephaly. However, unlike in MCPH, microcephaly is postnatal in Angelman syndrome patients. Our results show that UBE3A is a cell cycle regulated protein and its level peaks in mitosis. The shRNA knockdown of UBE3A in HEK293 cells led to many mitotic abnormalities including chromosome missegregation, abnormal cytokinesis and apoptosis. Thus our study links Angelman syndrome protein UBE3A to ASPM, centrosome and mitosis for the first time. We suggest that a defective chromosome segregation mechanism is responsible for the development of microcephaly in Angelman syndrome.     

MMS-induced primary aneuploidy and other genotoxic effects in mitotic cells of Aspergillus

The possibility of more than 1 target for genotoxic effects of methyl methanesulphonate (MMS) was investigated, using mitotic test systems of the fungus Aspergillus. Haploid and diploid strains were exposed, either as dormant conidia or during mitosis, and analysed for induced aneuploidy and effects on genetic segregation. MMS treatment of haploid strains resulted in dose-dependent increases of stable mutants with altered phenotypes and semi-stable unbalanced aberrations (presumably duplications). In addition, but only in dividing cells, MMS induced unstable aneuploids. These mostly were hyperhaploid with few extra chromosomes and could be identified by comparison with standard disomic phenotypes. When well-marked diploids were treated 3 types of effect could be distinguished, using genetic and phenotypic criteria: (1) Clastogenic and mutagenic effects which caused dose-dependent increases of partial aneuploids with various abnormal phenotypes. These showed secondary genetic segregation of all types and produced euploid normal sectors by eliminating damaged chromosome segments. In addition, but only in dividing nuclei, MMS induced 2 types of segregation: (2) Reciprocal crossing-over at high frequency, recognisable as half or quarter colonies of mutant colour and in some cases as 'twin spots' (i.e., complementary pairs); (3) Trisomics and other aneuploids which showed characteristic phenotypes and expected segregation of markers: the types recovered indicate random malsegregation of chromosomes (occasional deviations resulted from coincidence with induced crossing-over). These results suggest that MMS may have 2 (or more) targets for genotoxic effects: DNA, as evident from induced mutations and aberrations, and from induced recombination in dividing cells; some non-DNA target (nucleotide or protein) essential for nuclear division and susceptible to alkylation, resulting in malsegregation and primary aneuploidy.     

Primary microcephaly in two children born to mothers with complicated appendicitis or late appendectomy during pregnancy

BACKGROUND: The possible association between maternal appendicitis/appendectomy during pregnancy and congenital abnormalities in the offspring was studied. CASES: Two cases with primary microcephaly were born to mothers who had complicated appendicitis owing to the delay of appendectomy resulting in abscess/peritonitis associated with septicemia and fever in the second trimester of pregnancy. CONCLUSIONS: Delay in surgical intervention of appendicitis in pregnancy can result in maternal morbidity that may be associated with primary microcephaly in the offspring. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Systems and results of tests for chemical induction of mitotic malsegregation and aneuploidy in Aspergillus nidulans

In Aspergillus several types of test systems have been developed for detection of chemicals which induce aneuploidy and/or malsegregation of chromosomes. Results from 23 papers were reviewed in which numerical data for 42 chemicals had been reported. The test systems fall into two groups. One group includes all purely genetic tests that detect euploid mitotic segregants from heterozygous diploids and identify these either as products of malsegregation of chromosomes or as products of crossing-over (13 papers, several reviewed in detail previously; K?fer et al. (1982) and Scott et al. (1982)). The other group includes tests that treat haploid or diploid strains and detect aneuploids as unstable abnormally growing segregants which can be identified as specific disomics or trisomics by their characteristic phenotypes. In addition, such tests characterize abnormal segregants from heterozygous diploids by correlating phenotypes with patterns of genetic segregation in spontaneous euploid sectors. This analysis makes it possible to distinguish between induced primary aneuploidy of whole chromosomes and partial tri- or monosomy resulting from chromosome breakage and secondary spontaneous malsegregation (10 papers). Based on results of both types of tests, it is postulated that chemicals which cause increases of euploid malsegregants, but not of crossovers, normally induce aneuploids as primary products (as shown for 7 of the 14 cases). These include compounds which damage spindles or membranes (especially the well-known haploidizing agents) and generally are effective only when growing cells are exposed. (8 chemicals that may belong in this category could not be classified for certain, because information was insufficient.) On the other hand, chemicals which cause increases of all types of euploid segregants (11 cases), mostly induce drastic mutations and aberrations as primary effects and cause spontaneous malsegregation or crossing-over only as secondary events (as demonstrated for radiation-induced abnormals). In addition, a few chemicals were negative, because they increased only crossing-over or showed no increased segregation at all at concentrations which reduced survival or growth rate (9 cases). Recommendations are made for standardization of methods and protocols. New tester strains and specific procedures are outlined which should be useful for conclusive tests of chemicals that may induce aneuploidy.     

WDR62 localizes katanin at spindle poles to ensure synchronous chromosome segregation

Mutations in the WDR62 gene cause primary microcephaly, a pathological condition often associated with defective cell division that results in severe brain developmental defects. The precise function and localization of WDR62 within the mitotic spindle is, however, still under debate, as it has been proposed to act either at centrosomes or on the mitotic spindle. Here we explored the cellular functions of WDR62 in human epithelial cell lines using both short-term siRNA protein depletions and long-term CRISPR/Cas9 gene knockouts. We demonstrate that WDR62 localizes at spindle poles, promoting the recruitment of the microtubule-severing enzyme katanin. Depletion or loss of WDR62 stabilizes spindle microtubules due to insufficient microtubule minus-end depolymerization but does not affect plus-end microtubule dynamics. During chromosome segregation, WDR62 and katanin promote efficient poleward microtubule flux and favor the synchronicity of poleward movements in anaphase to prevent lagging chromosomes. We speculate that these lagging chromosomes might be linked to developmental defects in primary microcephaly.     

Socioeconomic disparities associated with symptomatic Zika virus infections in pregnancy and congenital microcephaly: A spatiotemporal analysis from Goiânia,Brazil (2016 to 2020)

The Zika virus (ZIKV) epidemic, which was followed by an unprecedented outbreak of congenital microcephaly, emerged in Brazil unevenly, with apparent pockets of susceptibility. The present study aimed to detect high-risk areas for ZIKV infection and microcephaly in Goiania, a large city of 1.5 million inhabitants in Central-West Brazil. Using geocoded surveillance data from the Brazilian Information System for Notifiable Diseases (SINAN) and from the Public Health Event Registry (RESP-microcefalia), we analyzed the spatiotemporal distribution and socioeconomic indicators of laboratory confirmed (RT-PCR and/or anti-ZIKV IgM ELISA) symptomatic ZIKV infections among pregnant women and clinically confirmed microcephaly in neonates, from 2016 to 2020. We investigated temporal patterns by estimating the risk of symptomatic maternal ZIKV infections and microcephaly per 1000 live births per month. We examined the spatial distribution of maternal ZIKV infections and microcephaly cases across the 63 subdistricts of Goiania by manually plotting the geographical coordinates. We used spatial scan statistics estimated by discrete Poisson models to detect high clusters of maternal ZIKV infection and microcephaly and compared the distributions by socioeconomic indicators measured at the subdistrict level. In total, 382 lab-confirmed cases of maternal ZIKV infections, and 31 cases of microcephaly were registered in the city of Goiania. More than 90% of maternal cases were reported between 2016 and 2017. The highest incidence of ZIKV cases among pregnant women occurred between February and April 2016. A similar pattern was observed in the following year, although with a lower number of cases, indicating seasonality for ZIKV infection, during the local rainy season. Most congenital microcephaly cases occurred with a time-lag of 6 to 7 months after the peak of maternal ZIKV infection. The highest estimated incidence of maternal ZIKV infections and microcephaly were 39.3 and 2.5 cases per 1000 livebirths, respectively. Districts with better socioeconomic indicators and with higher proportions of self-identified white inhabitants were associated with lower risks of maternal ZIKV infection. Overall, the findings indicate heterogeneity in the spatiotemporal patterns of maternal ZIKV infections and microcephaly, which were correlated with seasonality and included a high-risk geographic cluster. Our findings identified geographically and socio-economically underprivileged groups that would benefit from targeted interventions to reduce exposure to vector-borne infections.     

Microcephaly: general considerations and aids to nosology

Microcephaly is defined as an occipito-frontal head circumference (OFC) 2 or more standard deviations below the mean for age and sex using the new Roche et al. [Pediatrics 1987;79:706-712] charts, and corrected for parental OFC by the method of Weaver and Christian [J Pediatr 1980;96:990-994]. "Relative" microcephaly, i.e., a small head on a small child, may be associated with a much better intellectual prognosis than absolute microcephaly, although the average IQ of children with absolute microcephaly ascertained in a normal school system is normal when compared with that of appropriate control children. "Primary" microcephaly means an abnormal OFC at birth (corrected for gestational age and length), and "secondary" microcephaly a normal birth OFC with later, acquired microcephaly due to deceleration of brain growth reflecting infection, trauma, intoxication, metabolic disease, the Rett syndrome, or a true CNS degenerative disease. Some cases of syndromal microcephaly may be associated with normal intelligence including some "primordial dwarfs," children with Dubowitz syndrome, FAS, mild SC-Roberts syndrome, and an occasional Brachmann-de Lange individual. The nosology of (syndromal) microcephaly is extraordinarily complex and requires the assistance of special library resources and information retrieval expertise. At a minimum, it requires McKusick's Catalog of Mendelian Inheritance in Man (MIM); however, we find that our work is greatly enhanced by recently developed electronic databases such as MIM-online (OMIM), POSSUM, SYNDROME, and MEDLINE, as well. Three groups of syndromal and non-syndromal microcephaly are discussed selectively in order to illustrate the marvels of pleiotropy in human development and its abnormalities and the difficulties encountered in splitting and lumping entities with overlapping manifestations.     

Tests which distinguish induced crossing-over and aneuploidy from secondary segregation in Aspergillus treated with chloral hydrate or gamma-rays

A system of tests with the ascomycete Aspergillus nidulans was devised that can detect 3 primary effects of genotoxic agents: (1) increases in mitotic crossing-over; (2) induced aneuploidy; and (3) clastogenic effects which cause chromosomal imbalance. Conidia of a new diploid tester strain, heterozygous for 4 recessive markers which alter conidial color, are treated and plated onto nonselective media. In cases of induced crossing-over, large color segments are found in normal green colonies, frequently adjacent to reciprocal twin segments. In contrast, both malsegregation and chromosome breakage produce unbalanced types which grow poorly and segregate further. Cases with yellow segregants are replated and their secondary diploid sectors tested for markers which are located on both chromosome arms in coupling with yA. Induced aneuploidy can be distinguished from chromosome breakage by the pattern of marker segregation. Any aneuploid type will produce euploid sectors solely by segregation of whole chromosomes; trisomic colonies (yA / yA / +) will show 1:2 ratios for yellow (homozygous yA) to parental green (yA/+) sectors and have characteristic phenotypes. Other induced unbalanced types, if heterozygous for deletions or aberrations may produce yellow diploid sectors by secondary crossing-over as well as by nondisjunction and such cases show unique patterns of genetic segregation and non- predictable phenotypes. As a complementary test, haploid strains are treated and induced abnormally growing types are replated and classified by phenotype. Aneuploids are unstable and produce many normal sectors, and some of these disomic or trisomic types can be visually identified.In contrast, induced deletions are lethal, and duplications or 'morphological' mutants show much more stable abnormal phenotypes. This test system was used to characterize the primary effects of gamma-rays and chloral hydrate. Results and evidence were as follows: (1) A dose-dependent increase of color segments resulting from reciprocal crossing-over was found after treatment of dividing nuclei in germinating diploid conidia with gamma-rays, but not with chloral hydrate. (2) Highly aneuploid and polyploid types were induced in diploid and haploid germinating conidia by chloral hydrate but not to any significant extent by gamma-rays. (3) gamma-Rays caused a dose- dependent increase off abnormally growing colonies when dormant or germinating diploid conidia were treated. These colonies produced secondary euploid sectors by spontaneous nondisjunction and frequently also by crossing-over, which provided evidence for induced semidominant and recessive lethal mutations of many types.     

Transgenic rapeseed plants obtained by the microinjection of DNA into microspore-derived embryoids

Summary A novel method in the field of genetic engineering of higher plants is presented: microinjection into multicellular structures which have a high competence for plant regeneration through embryogenesis. Microspore-derived embryoids of Brassica napus L. were individually selected and microinjected with NPT II gene constructions. High frequency regeneration of haploid plants through embryogenesis was achieved within 8 weeks. Transformation efficiencies between 27% and 51% were determined by DNA dot blot analysis of primary regenerants. Stable integration of fulllength microinjected genes into high molecular weight DNA was proven by Southern analysis of genomic DNA isolated from regenerated plants. Transformed plants were tested for expression of the NPT II gene by enzyme assay. The chimeric nature of the primary regenerants was demonstrated after their in vitro segregation through secondary embryogenesis into pure transformants.     

The effect of reciprocal translocations on segregation and multivalent formation in autotetraploids of rye,Secale cereale

Chromosomal segregation, and the frequency of large multivalents in Secale cereale were studied in autotetraploid duplex translocation heterozygotes. Models for estimating expected segregations and frequencies of multivalents were developed incorporating the probabilities of different chromosomal segments being bound by chiasmata. It appeared that the segregation of the two translocations tested fitted quite well the expected corrected segregation ratio of approximately 1: 11.5: 1, suggesting that induced preferential pairing was not strong enough to enhance preferential segregation resulting from random translocation segregation. Interspecific hybrids with S. montanum carrying the same translocations showed strong preferential pairing, i.e. significant deviation from the expected ratios.Three translocations tested (two not tested for segregation) showed a decrease in multivalent frequency mainly attributable to preferential pairing, especially in cases where the breakpoint was near one chromosome end. Possible reasons why preferential pairing is expressed here and not in the segregations are discussed.     

Host-parasite coevolution and selection on sex through the effects of segregation

The advantage of producing novel variation to keep apace of coevolving species has been invoked as a major explanation for the evolution and maintenance of sex (the Red Queen hypothesis). Recent theoretical investigations of the Red Queen hypothesis have focused on the effects of recombination in haploid species, finding that species interactions rarely favor the evolution of sex unless selection is strong. Yet by focusing on haploids, these studies have ignored a potential advantage of sex in diploids: generating novel combinations of alleles at a particular locus through segregation. Here we investigate models of host-parasite coevolution in diploid species to determine whether the advantages of segregation might rescue the Red Queen hypothesis as a more general explanation for the evolution of sex. We find that the effects of segregation can favor the evolution of sex but only under some models of infection and some parameter combinations, almost always requiring inbreeding. In all other cases, the effects of segregation on selected loci favor reductions in the frequency of sex. In cases where segregation and recombination act in opposite directions, we found that the effects of segregation dominate as an evolutionary force acting on sex in diploids.     

Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling

Ataxia telangiectasia and Rad3-related (ATR) protein, a kinase that regulates a DNA damage-response pathway, is mutated in ATR-Seckel syndrome (ATR-SS), a disorder characterized by severe microcephaly and growth delay. Impaired ATR signaling is also observed in cell lines from additional disorders characterized by microcephaly and growth delay, including non-ATR-SS, Nijmegen breakage syndrome, and MCPH1 (microcephaly, primary autosomal recessive, 1)-dependent primary microcephaly. Here, we examined ATR-pathway function in cell lines from three haploinsufficient contiguous gene-deletion disorders--a subset of blepharophimosis-ptosis-epicanthus inversus syndrome, Miller-Dieker lissencephaly syndrome, and Williams-Beuren syndrome--in which the deleted region encompasses ATR, RPA1, and RFC2, respectively. These three genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, we describe ATR signaling as a pathway unusually sensitive to haploinsufficiency and identify three further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR-pathway dysfunction with the presence of microcephaly and growth delay strongly suggests a causal relationship.     

Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter.

Primary (or "true") microcephaly is inherited as an autosomal recessive trait and is thought to be genetically heterogeneous. Using autozygosity mapping, we have identified a genetic locus (MCPH1) for primary microcephaly, at chromosome 8p22-pter, in two consanguineous families of Pakistani origin. Our results indicate that the gene lies within a 13-cM region between the markers D8S1824 and D8S1825 (maximum multipoint LOD score of 8.1 at D8S277). In addition, we have demonstrated the genetic heterogeneity of this condition by analyzing a total of nine consanguineous families with primary microcephaly.     

Warburg micro syndrome in two children from a highly inbred Turkish family

Warburg Micro syndrome (WMS) was first reported by Warburg in 1993. The cardinal features are microcephaly, microphthalmia, congenital cataract and intellectual disability. We report on two children from a highly inbred family with microcephaly, congenital cataract, optic atrophy, hypotonia and severe psychomotor retardation. This phenotype is similar to other reported rare entities and especially to the family reported by Warburg. Four other children in the same family may also have been affected. In this report, the symptoms and features of our cases are compared with the Warburg Micro syndrome patients in literature.     

What primary microcephaly can tell us about brain growth

Autosomal recessive primary microcephaly (MCPH) is a neuro-developmental disorder that causes a great reduction in brain growth in utero. MCPH is hypothesized to be a primary disorder of neurogenic mitosis, leading to reduced neuron number. Hence, MCPH proteins are likely to be important components of cellular pathways regulating human brain size. At least six genes can cause this disorder and four of these have recently been identified: autosomal recessive primary microcephaly 1 (MCPH1), abnormal spindle-like, microcephaly associated (ASPM), cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) and centromere protein J (CENPJ). Whereas aberration of ASPM is the most common cause of MCPH, MCPH1 patients can be more readily diagnosed by the finding of increased numbers of "prophase-like cells" on routine cytogenetic investigation. Three MCPH proteins are centrosomal components but have apparently diverse roles that affect mitosis. There is accumulating evidence that evolutionary changes to the MCPH genes have contributed to the large brain size seen in primates, particularly humans. The aim of this article is to review what has been learnt about the rare condition primary microcephaly and the information this provides about normal brain growth.     

“One feels anger to know there is no one to help us!”. Perceptions of mothers of children with Zika virus-associated microcephaly in Caribbean Colombia: A qualitative study

BackgroundThe epidemic of Zika virus (ZIKV) was associated with a sudden and unprecedented increase in infants born with microcephaly. Colombia was the second most affected country by the epidemic in the Americas. Primary caregivers of children with ZIKV-associated microcephaly, their mothers mainly, were at higher risk of suffering anxiety and depression. Often, these women were stigmatized and abandoned by their partners, relatives, and communities.Methodology/Principal findingsThis study aimed to understand the perceptions about ZIKV infection among mothers of children born with microcephaly during the ZIKV epidemic in Caribbean Colombia, and the barriers and facilitators affecting child health follow-up. An exploratory qualitative study, based on Phenomenology and Grounded Theory, was conducted in Caribbean Colombia. Data were collected through In-Depth Interviews (IDI) from women who delivered a baby with microcephaly during the ZIKV epidemic at Clínica Salud Social, Sincelejo, Sucre District (N = 11). The themes that emerged during the interviews included experiences from their lives before pregnancy; knowledge about ZIKV; experiences and perceptions when diagnosed; considering a possible termination of pregnancy, and children’s clinical follow-up. In some cases, women reported having been told they were having a baby with microcephaly but decided not to terminate the pregnancy; while in other cases, women found out about their newborn’s microcephaly condition only at birth. The main barriers encountered by participants during children’s follow-up included the lack of psychosocial and economic support, the stigmatization and abandonment by some partners and relatives, and the frustration of seeing the impaired development of their children.ConclusionsThis study contributed to identifying the social, medical, psychological, and economic needs of families with children affected by the ZIKV epidemic. Commitment and action by local and national governments, and international bodies, is required to ensure sustained and quality health services by affected children and their families.     

The mechanism of secondary nondisjunction in Drosophila melanogaster females

Bridges (1916) observed that X chromosome nondisjunction was much more frequent in XXY females than it was in genetically normal XX females. In addition, virtually all cases of X nondisjunction in XXY females were due to XX <--> Y segregational events in oocytes in which the two X chromosomes had failed to undergo crossing over. He referred to these XX <--> Y segregation events as "secondary nondisjunction." Cooper (1948) proposed that secondary nondisjunction results from the formation of an X-Y-X trivalent, such that the Y chromosome directs the segregation of two achiasmate X chromosomes to opposite poles on the first meiotic spindle. Using in situ hybridization to X and YL chromosomal satellite sequences, we demonstrate that XX <--> Y segregations are indeed presaged by physical associations of the X and Y chromosomal heterochromatin. The physical colocalization of the three sex chromosomes is observed in virtually all oocytes in early prophase and maintained at high frequency until midprophase in all genotypes examined. Although these XXY associations are usually dissolved by late prophase in oocytes that undergo X chromosomal crossing over, they are maintained throughout prophase in oocytes with nonexchange X chromosomes. The persistence of such XXY associations in the absence of exchange presumably facilitates the segregation of the two X chromosomes and the Y chromosome to opposite poles on the developing meiotic spindle. Moreover, the observation that XXY pairings are dissolved at the end of pachytene in oocytes that do undergo X chromosomal crossing over demonstrates that exchanges can alter heterochromatic (and thus presumably centromeric) associations during meiotic prophase.     

Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability,developmental delay,dysmorphic feature and microcephaly

Intellectual developmental disorder with abnormal behavior, microcephaly and short stature (IDDABS), (OMIM# 618342) is an autosomal recessive condition described as developmental delay, poor or absent speech, intellectual disability, short stature, mild to progressive microcephaly, delayed psychomotor development, hyperactivity, seizure, along with mild to swear aggressive behavior. Homozygous frameshift mutation in Pseudouridine Synthase 7, Putative; (PUS7) OMIM# 616,261 NM_019042.3 and splice acceptor variants in Alpha-Aminoadipic Semialdehyde Synthase; (AASS) OMIM# 605,113 NM_005763.3 was funded. Whole exome sequencing (WES) technique was used as tool to identify the molecular diagnostic test. Different bioinformatics analysis done for WES data and we identified two novel mutations one as frameshift mutation c.606_607delGA, p.Ser282CysfsTer9 in the PUS7 gene and splice acceptor variants c.1767–1 G > A in the AASS gene has been reported. The pattern of family segregation maintained the pathogenicity of this variation associated with abnormal behavior, intellectual developmental disorder, microcephaly along with short stature IDDABS. Further, the WES data was validated in the family having other affected individuals and healthy controls (n = 100) was done using Sanger sequencing. Finally, our results further explained the role of WES in the disease diagnosis and elucidated that the mutation in PUS7 and AASS genes may lead an important role for the development of IDDABS in Saudi family.